WO2019233308A1 - 一种预测拮抗剂方案下受试者卵巢低反应概率的系统以及指导促性腺激素起始用药剂量选择的系统 - Google Patents

一种预测拮抗剂方案下受试者卵巢低反应概率的系统以及指导促性腺激素起始用药剂量选择的系统 Download PDF

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WO2019233308A1
WO2019233308A1 PCT/CN2019/088679 CN2019088679W WO2019233308A1 WO 2019233308 A1 WO2019233308 A1 WO 2019233308A1 CN 2019088679 W CN2019088679 W CN 2019088679W WO 2019233308 A1 WO2019233308 A1 WO 2019233308A1
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subject
probability
level
ovarian response
hormone
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PCT/CN2019/088679
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English (en)
French (fr)
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李蓉
徐慧玉
冯国双
韩勇
乔杰
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广州市康润生物科技有限公司
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H70/00—ICT specially adapted for the handling or processing of medical references
    • G16H70/40—ICT specially adapted for the handling or processing of medical references relating to drugs, e.g. their side effects or intended usage

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  • the present invention relates to a system for predicting low ovarian response in a subject under an antagonist dosing regimen, and a system for guiding the starting dose range of gonadotropin (Gn).
  • Predicting ovarian response before COS, and administering an appropriate starting dose of an exogenous ovulation-stimulating drug (Gn) is currently the only clinically accepted method to avoid low ovarian response.
  • Gn exogenous ovulation-stimulating drug
  • a variety of markers have been used worldwide to assess low ovarian response, including age, follicle stimulating hormone (bFSH) levels for 2-4 days of menstruation, sinus follicle count (AFC), anti-Muller hormone (AMH), and menstruation 2 -4 days of estrogen level (bE2) and so on.
  • bFSH follicle stimulating hormone
  • AFC sinus follicle count
  • AMH anti-Muller hormone
  • bE2 menstruation 2 -4 days of estrogen level
  • GnRH gonadotropin releasing hormone
  • the present invention intends to provide a system capable of accurately, conveniently, and rapidly predicting a low ovarian response, and to provide a system capable of accurately, conveniently, and rapidly guiding medications for a patient with a low ovarian response.
  • the present invention relates to the following:
  • a system for predicting the probability of a low ovarian response in a subject comprising:
  • a data acquisition module which is used to obtain data on the subject's age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC);
  • a module for calculating a probability of occurrence of a low ovarian response which is configured to calculate the foregoing information obtained in the data acquisition module, so as to calculate or predict the probability of occurrence of a low ovarian response in the subject.
  • the subject is administered an exogenous ovulation-stimulating drug (Gn) on the second or third day of the menstrual cycle, and is administered 5-7 days after the administration of the exogenous gonadotropin (Gn)
  • Gn exogenous gonadotropin
  • the subject's age, subject's anti-Mullerian hormone (AMH) level, subject's follicle stimulating hormone (FSH) level, and subject's sinus follicle count ( AFC) data were converted into binary variables to calculate the probability of a subject's low ovarian response.
  • the receiver operating characteristic (ROC) curve is used to detect age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) Cutoff point, and based on the cutoff value of the cutoff point, age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) are converted into binary classification variables, so as to use
  • the dichotomous variable is used to calculate the probability that a subject will experience a low ovarian response.
  • the anti-Mullerian hormone (AMH) level refers to the anti-Mullerian hormone concentration in the venous blood of a female subject for 2-4 days
  • the follicle stimulating hormone (FSH) level refers to a female subject
  • the sinus follicle count (AFC) refers to the vaginal B-ultrasound count. The number of all visible follicles.
  • the cut-off point for the age is 35 years
  • the cut-off point for the anti-Mullerian hormone (AMH) level is 0.93ng / ml
  • the cut-off point for the follicle stimulating hormone (FSH) level is 9.1IU / L
  • the cutoff value of the sinus follicle count (AFC) is 8.
  • the module for calculating the probability of low ovarian response pre-stores the subject's age based on the subject in the existing database, the subject's anti-Mullerian hormone (AMH) level, and the subject's follicle stimulating hormone (FSH)
  • the formula used to calculate the probability of occurrence of low ovarian response is fitted by a binary classification variable converted from the data of the level and the sinus follicle count (AFC) of the subject.
  • i is any value selected from -1.786 to -0.499
  • a is any value selected from 0.063 to 1.342
  • b is any value selected from -2.542 to -1.056
  • c is selected from 0.548 to 1.838
  • a system for guiding the determination of gonadotropin dosage in a patient comprising:
  • a data acquisition module which is used to obtain data on the subject's age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC);
  • a module for calculating a probability of occurrence of a low ovarian response which is configured to calculate the foregoing information obtained in the data acquisition module, thereby calculating or predicting the probability of occurrence of a ovarian low response in the subject;
  • a grouping module in which a grouping basis is pre-stored, and according to the grouping basis, the probability of low ovarian response of the subjects calculated by the module for calculating the probability of occurrence of low ovarian response is grouped;
  • the recommended module for the starting dose of exogenous gonadotropin (Gn) is based on the grouping module to recommend the starting dose of Gn for the group divided by the subjects.
  • the subject is administered an exogenous ovulation-stimulating drug (Gn) on the second or third day of the menstrual cycle, and is administered 5-7 days after the administration of the exogenous gonadotropin (Gn)
  • Gn exogenous gonadotropin
  • the pre-existing grouping basis in the grouping module is a grouping basis established for the occurrence of a low ovarian response probability based on whether the interaction between the starting dose of Gn and the predicted low ovarian response probability is meaningful using an existing database.
  • the pre-stored grouping basis in the grouping module is:
  • the probability of a subject having a low ovarian response is ⁇ 5%
  • the subject's age, subject's anti-Mullerian hormone (AMH) level, subject's follicle stimulating hormone (FSH) level, and subject's sinus follicle count ( AFC) data were converted into binary variables to calculate the probability of a subject's low ovarian response.
  • the receiver operating characteristic (ROC) curve is used to detect age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) Cutoff point, and based on the cutoff value of the cutoff point, age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) are converted into binary classification variables, so as to use
  • the dichotomous variable is used to calculate the probability that a subject will experience a low ovarian response.
  • the anti-Mullerian hormone (AMH) level refers to the anti-Mullerian hormone concentration in the venous blood of a female subject for 2-4 days
  • the follicle stimulating hormone (FSH) level refers to a female subject
  • the sinus follicle count (AFC) refers to the vaginal B-ultrasound count. The number of follicles.
  • the cut-off point for the age is 35 years
  • the cut-off point for the anti-Mullerian hormone (AMH) level is 0.93ng / ml
  • the cut-off point for the follicle stimulating hormone (FSH) level is 9.1IU / L
  • the cutoff value of the sinus follicle count (AFC) is 8.
  • the module for calculating the probability of low ovarian response pre-stores the subject's age based on the subject in the existing database, the subject's anti-Mullerian hormone (AMH) level, and the subject's follicle stimulating hormone (FSH)
  • the formula used to calculate the probability of occurrence of low ovarian response is fitted by a binary classification variable converted from the data of the level and the sinus follicle count (AFC) of the subject.
  • the formula is the following formula one:
  • i is any value selected from -1.786 to -0.499
  • a is any value selected from 0.063 to 1.342
  • b is any value selected from -2.542 to -1.056
  • c is selected from 0.548 to 1.838
  • a method for predicting the probability of a low ovarian response in a subject comprising:
  • a data collection step in which the data of the subject's age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) are obtained;
  • AMH anti-Mullerian hormone
  • FSH follicle stimulating hormone
  • AFC sinus follicle count
  • a step of calculating the probability of a low ovarian response in which the age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, sinus follicle count (AFC) )
  • the data are calculated to calculate or predict the probability of a low ovarian response in the subject.
  • the subject is administered an exogenous ovulation-stimulating drug (Gn) on the second or third day of the menstrual cycle, and is administered 5-7 days after the administration of the exogenous gonadotropin (Gn)
  • Gn exogenous gonadotropin
  • the subject's age, subject's anti-Mullerian hormone (AMH) level, subject's follicle stimulating hormone (FSH) level, and subject's sinus follicle count ( AFC) data is converted into binary variables, and the converted binary variables are used to calculate or predict the probability of a subject's low ovarian response.
  • AMD anti-Mullerian hormone
  • FSH follicle stimulating hormone
  • AFC sinus follicle count
  • the receiver operating characteristic (ROC) curve was used to detect age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) Cutoff point, and based on the cutoff value of the cutoff point, age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) are converted into binary classification variables, so as to use
  • the dichotomous variable is used to calculate the probability that a subject will experience a low ovarian response.
  • the anti-Mullerian hormone (AMH) level refers to the anti-Mullerian hormone concentration in the venous blood of a female subject for 2-4 days
  • the follicle stimulating hormone (FSH) level refers to a female subject
  • the sinus follicle count (AFC) refers to the vaginal B-ultrasound count. The number of all visible follicles.
  • the cut-off point for the age is 35 years
  • the cut-off point for the anti-Mullerian hormone (AMH) level is 0.93ng / ml
  • the cut-off point for the follicle stimulating hormone (FSH) level is 9.1IU / L
  • the cutoff value of the sinus follicle count (AFC) is 8.
  • the subject's age based on the subject in the existing database the subject's anti-Mullerian hormone (AMH) level, and the subject's follicle stimulating hormone (FSH) are used.
  • AMH anti-Mullerian hormone
  • FSH follicle stimulating hormone
  • AFC sinus follicle count
  • i is any value selected from -1.786 to -0.499
  • a is any value selected from 0.063 to 1.342
  • b is any value selected from -2.542 to -1.056
  • c is selected from 0.548 to 1.838
  • a method for guiding medication in patients with low ovarian response comprising:
  • a data collection step in which the data of the subject's age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) are obtained;
  • AMH anti-Mullerian hormone
  • FSH follicle stimulating hormone
  • AFC sinus follicle count
  • grouping according to the calculated probability that the subject has a low ovarian response; and recommending the starting dose of Gn to the subject according to the grouping.
  • the subject is administered an exogenous ovulation-stimulating drug (Gn) on the second or third day of the menstrual cycle, and 5-7 days after the administration of the exogenous ovulation-stimulating drug (Gn).
  • the pre-existing grouping basis is based on the existing database and the grouping basis based on whether the interaction between the starting dose of Gn and the predicted probability of low ovarian response is meaningful and the probability of low-level ovarian reaction occurring.
  • the pre-stored grouping basis is:
  • the probability of a subject having a low ovarian response is ⁇ 5%
  • the subject's age, subject's anti-Mullerian hormone (AMH) level, subject's follicle stimulating hormone (FSH) level, and subject's sinus follicle count are used.
  • AFC AFC data is converted into a binary variable to calculate the probability of a subject's low ovarian response.
  • the receiver operating characteristic (ROC) curve was used to detect age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC). Cutoff point, and according to the cutoff value of the cutoff point, age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) are converted into two categorical variables to use all These two categorical variables are used to calculate the probability of a subject's low ovarian response.
  • AMD anti-Mullerian hormone
  • FSH follicle stimulating hormone
  • AFC sinus follicle count
  • the anti-Mullerian hormone (AMH) level refers to the anti-Mullerian hormone concentration in the venous blood of a female subject for 2-4 days
  • the follicle stimulating hormone (FSH) level refers to a female subject
  • the sinus follicle count (AFC) refers to the vaginal B-ultrasound count. The number of all visible follicles.
  • the cut-off point for the age is 35 years
  • the cut-off point for the anti-Mullerian hormone (AMH) level is 0.93ng / ml
  • the cut-off point for the follicle stimulating hormone (FSH) level is 9.1IU / L
  • the cutoff value of the sinus follicle count (AFC) is 8.
  • the subject's age based on the subject in the existing database the subject's anti-Mullerian hormone (AMH) level, and the subject's follicle stimulating hormone (FSH) are used.
  • AMH anti-Mullerian hormone
  • FSH follicle stimulating hormone
  • AFC sinus follicle count
  • i is any value selected from -1.786 to -0.499
  • a is any value selected from 0.063 to 1.342
  • b is any value selected from -2.542 to -1.056
  • c is selected from 0.548 to 1.838
  • the present invention intends to obtain a reliable system for predicting low ovarian response, and an effective method for guiding patients with low ovarian response.
  • the system uses such a system to classify subjects into different groups according to the probability of occurrence of a low ovarian response, and then assigns a dosage regimen to the subject according to the group of the subject.
  • the system for predicting the occurrence of hypoovarian response in a subject of the present invention can be used first to predict the probability of occurrence of hypoovarian response in a subject.
  • the occurrence probability of low ovarian response can be predicted, so that ovarian reserve can be evaluated.
  • the clinical evaluation index of ovarian reserve is also an indicator to predict low ovarian response, and when making a diagnosis of decreased ovarian reserve Clinicians also use the diagnostic criteria for low ovarian response. Because the definition of ovarian reserve refers to the number of primitive follicles in the ovarian cortex, the number of primitive follicles cannot be evaluated non-invasively.
  • the grouping module can be used to achieve the probability of low ovarian response to the subject.
  • the system's preset grouping criteria are: subjects with low response probability ⁇ 5% group, 5% ⁇ the probability of subjects with low ovarian response ⁇ 20% group, 20% ⁇ subjects with low ovarian response Groups with probability ⁇ 50% and low response probability greater than or equal to 50%.
  • the recommended dosage module of the drug dose can be used to achieve the recommended starting dose of the exogenous ovulation-stimulating drug (Gn) for subjects belonging to different groups.
  • Utilizing the system of the present invention can prompt doctors to gradually increase the starting dose of Gn according to the order of the predicted low response probability of the patient, in order to achieve the best potency ratio, which can be achieved through shorter treatment cycles and lower The cost of treatment to improve patients' ovarian response levels.
  • the inventors of the present invention applied the four indexes of AMH level, age, 2-4 days menstrual FSH level, and AFC of vaginal B ultrasound count in 2-4 menstrual periods to the low ovarian response in the antagonist scheme.
  • the population was predicted based on the interaction between the predicted probability of low ovarian response and the starting dose of exogenous gonadotropin (Gn), and recommendations for the starting dose of Gn were given.
  • Gn exogenous gonadotropin
  • FIG. 6 is a regression model diagram of the starting dose of Gn, the predicted probability of LOR, and the interaction effect between them.
  • Endometriosis refers to a common gynecological disease in women formed when active endometrial cells are planted outside the endometrium. Endometrial cells should have grown in the uterine cavity, but because the uterine cavity communicates with the pelvic cavity through the fallopian tube, the endometrial cells can enter the pelvic cavity through the fallopian tube to grow ectopically.
  • the main pathological changes of endometriosis are ectopic endometrial periodic bleeding and fibrosis of surrounding tissues, forming ectopic nodules. Dysmenorrhea, chronic pelvic pain, abnormal menstruation and infertility are the main symptoms.
  • Fallopian tube infertility means that due to the important role of fallopian tubes to transport sperm, pick up eggs and transport fertilized eggs to the uterine cavity, tubal dysfunction or dysfunction becomes the main cause of female infertility.
  • the cause of tubal obstruction or dysfunction is acute and chronic fallopian tube inflammation.
  • unexplained infertility is defined as a couple who have normal ovulation tests, fallopian tube patency tests, and semen analysis tests that show normal but have a history of repeated pregnancy failures.
  • Continuous variables In statistics, variables can be divided into continuous variables and categorical variables according to whether the values of the variables are continuous.
  • a variable that can be arbitrarily taken within a certain interval is called a continuous variable, and its value is continuous.
  • Two adjacent values can be divided infinitely, and an unlimited number of values can be taken.
  • the dimensions of production parts, anthropometric height, weight, bust, etc. are continuous variables, and their values can only be obtained by measurement or measurement.
  • discrete variables are those whose values can only be calculated using natural numbers or integer units. For example, the number of enterprises, the number of employees, and the number of equipment can only be counted in units of measurement. The value of this variable is generally obtained by counting.
  • Categorical variables refer to variables such as geographic location and demographics, and their role is to group survey respondents. Descriptive variables describe the differences between one customer group and other customer groups. Most categorical variables are also descriptive variables. Categorical variables can be divided into two categories: unordered categorical variables and ordered categorical variables. Among them, unordered categorical variable (unordered category variable) means that there is no difference in degree and order between the classified categories or attributes. It can be divided into 1 binomial classification, such as gender (male, female), drug response (negative and positive), etc .; 2 multiple classifications, such as blood type (O, A, B, AB), occupation (industrial, agricultural, Business, education, military). There is a degree of difference between the ordinal category variables.
  • urine glucose test results are classified by-, ⁇ , +, ++, +++; curative effects are classified by cure, marked effect, improvement, and ineffectiveness.
  • ordinal categorical variables they should be grouped according to rank order, the number of observation units in each group should be counted, and a frequency table of ordinal variables (each rank) should be compiled. The obtained data is called rank data.
  • Variable types are not static. Depending on the purpose of the research, various types of variables can be converted. For example, the amount of hemoglobin (g / L) is a numerical variable. If the hemoglobin is divided into normal and low levels, it can be analyzed by binomial data. If it is classified as severe anemia, moderate anemia, mild anemia, normal, hemoglobin When the increase is divided into five levels, it can be analyzed according to the level data. Sometimes categorical data can also be quantified. If the nausea response of a patient can be expressed as 0, 1, 2, 3, it can be analyzed by numerical variable data (quantitative data).
  • the invention relates to a system for predicting the probability of low ovarian response in a subject, which comprises:
  • a data acquisition module which is used to obtain data on the subject's age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC);
  • a module for calculating a probability of occurrence of a low ovarian response which is configured to calculate the foregoing information obtained in the data acquisition module, thereby calculating a probability of occurrence of a low ovarian response in the subject.
  • the subject is administered exogenous gonadotropin (Gn) on the second or third day of the menstrual cycle, and after exogenous gonadotropin (Gn) is administered Subjects administered an antagonist of gonadotropin-releasing hormone (GnRH) for 5-7 days.
  • Gn gonadotropin
  • GnRH gonadotropin-releasing hormone
  • the low ovarian response in the present invention refers to the administration of exogenous gonadotropin (Gn) on the second or third day of the menstrual cycle as described above, and the administration of exogenous gonadotropin (Gn) Under the condition of subjects who were administered antagonists of gonadotropin-releasing hormone (GnRH) from 5 to 7 days, less than 5 (ie, 0-4) oocytes were obtained on the day of egg retrieval, and low ovarian response was predicted to occur
  • the probability refers to the data calculated by the system of the present invention.
  • exogenous gonadotropin (Gn) treatment is started on the second or third day of the menstrual cycle.
  • the starting dose is based on age, BMI (that is, body mass index, which is a number obtained by dividing weight in kilograms by height in meters squared, which is a standard commonly used in the world to measure human body fat and thin and whether it is healthy), menstruation 2 -4 days to choose from FSH and AFC levels.
  • BMI body mass index
  • menstruation 2 -4 days to choose from FSH and AFC levels.
  • the initial dose of Gn was adjusted based on ultrasound observations and serum E2 levels.
  • GnRH antagonist treatment begins on days 5-7 of the stimulus with a growing follicle diameter of 10-12 mm.
  • hCG When at least 2 dominant follicles (diameter 18 mm in diameter) are visible by ultrasound, hCG of 5000-10000 IU is given to trigger final oocyte maturation. Egg retrieval was performed 36 hours after hCG administration. 1-3 embryos are transferred or cryopreserved. Progesterone support is then provided for the luteal phase.
  • the exogenous gonadotropin (Gn) is exogenous human recombinant follicle stimulating hormone (rFSH).
  • the subject's age, subject's anti-Mullerian hormone (AMH) level, subject's follicle stimulating hormone (FSH) level, and subject's sinus follicle count ( (AFC) data into binary variables to calculate or predict the probability of a subject's low ovarian response.
  • AMD anti-Mullerian hormone
  • FSH follicle stimulating hormone
  • AFC sinus follicle count
  • Anti-Mullerian hormone is a hormone secreted by the granulosa cells of the ovarian follicles.
  • Female babies from the fetal period start to produce AMH from the 9th month of the stool.
  • Follicle-stimulating hormone is a hormone secreted by basophils in the anterior pituitary gland.
  • the component is a glycoprotein, which mainly promotes follicle maturation.
  • FSH can promote the proliferation and differentiation of follicular granulosa cells and promote the growth of the entire ovary. And its action on the seminiferous tubules of the testis can promote sperm formation.
  • FSH is pulsed in the body, and women change with the menstrual cycle.
  • Determining FSH in serum is of great significance for understanding pituitary endocrine function, indirect understanding of ovarian functional status, assessment of ovarian reserve and ovarian reactivity, and formulation of ovulation-promoting medication doses for the diagnosis and treatment of infertility and endocrine diseases.
  • Sinus follicle count refers to the number of all visible follicles with a diameter of 2-8 mm in the two ovaries between 2-4 days of menstruation. AFC can measure and count follicles by ultrasound.
  • the anti-Mullerian hormone (AMH) level refers to the concentration of anti-Mullerian hormone in a venous blood serum sample of a female subject's menstruation for 2-4 days
  • the follicle stimulating hormone (FSH) level refers to a female
  • the sinus follicle count (AFC) refers to the vaginal B-count. The number of all visible follicles at 8mm.
  • the receiver operating characteristic (ROC) curve is used to detect age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) Cutoff point, and based on the cutoff value of the cutoff point, age, anti-Mullerian hormone (AMH) level, follicle stimulating hormone (FSH) level, and sinus follicle count (AFC) are converted into binary classification variables, so as to use All of the two categorical variables are brought into the above formula to calculate the probability of a subject's low ovarian response.
  • ROC receiver operating characteristic
  • the cut-off point for age is 35 years old
  • the cut-off point for anti-Mullerian hormone (AMH) level is 0.93ng / ml
  • the cut-off point for follicle stimulating hormone (FSH) level is 9.1IU / L
  • the cutoff value of the sinus follicle count (AFC) is 8.
  • the module for calculating the probability of low ovarian response pre-stores the subject's age based on the subject in the existing database, the subject's anti-Mullerian hormone (AMH) level, and the subject's follicle stimulating hormone (FSH)
  • the formula used to calculate the probability of occurrence of low ovarian response is fitted by a binary classification variable converted from the data of the level and the sinus follicle count (AFC) of the subject.
  • the existing database refers to a database that can be obtained of subjects who are undergoing treatment or have previously received treatment that meet the following inclusion and exclusion criteria. There is no agreement on the sample size of the database. As large as possible, for example, 100 subjects, 200 subjects, and 300 subjects may be used, preferably 400 subjects or more, and more preferably 500 subjects or more. In a specific embodiment, an existing database composed of 561 samples is used.
  • the above inclusion and exclusion criteria are as follows: women between the ages of 20 and 45, body mass index (BMI) ⁇ 30, six consecutive menstrual cycles of 25 to 45 days, and bilateral ovaries assessed by vaginal ultrasound The morphology is normal, and the number of previous IVF / ICSI-ET cycles is ⁇ 2.
  • Exclusion criteria hydrosalpinx, AFC unilateral ovaries> 20, polycystic ovary syndrome, other untreated metabolic or endocrine diseases, previous surgery for the ovaries or uterine cavity, intrauterine abnormalities, within 3 months of pregnancy, Genes who smoked, used oral contraceptives or other hormones within the previous two months, had previously undergone radiotherapy or chemotherapy, and received PGD (preimplantation genetic diagnosis) / PGS (preimplantation genetic screening) treatment genes Couple having a diagnosis.
  • the module for calculating the probability of low ovarian response uses the following formula to calculate the probability of low ovarian response based on the data obtained from the data acquisition module:
  • i is any value selected from -1.786 to -0.499
  • a is any value selected from 0.063 to 1.342
  • b is any value selected from -2.542 to -1.056
  • c is selected from 0.548 to 1.838
  • the system for guiding medication for patients with low ovarian response includes, in addition to the above-mentioned data acquisition module and the above-mentioned module for calculating the probability of occurrence of ovarian low response, the system also includes:
  • a grouping module in which a grouping basis is pre-stored, and according to the grouping basis, the probability of low ovarian response of the subjects calculated by the module for calculating the probability of occurrence of low ovarian response is grouped; specifically, it is based on a preset
  • the database divides the population into four groups based on the predicted low response probability. After the subjects get the calculated low response rate, the system will automatically assign them to the corresponding group, and
  • the recommended module for the starting dose of exogenous gonadotropin (Gn) is based on the grouping module to recommend the starting dose of Gn for the group divided by the subjects.
  • the above-mentioned pre-existing grouping basis is based on the use of existing databases and based on whether the interaction between the initial dose of Gn and the predicted probability of a low ovarian response is meaningful, and the grouping basis for the occurrence of a low-ovarian response probability.
  • the subjects in the existing database are used to determine the probability of a low ovarian response based on whether the interaction between the Gn starting dose of these subjects and the predicted probability of a low ovarian response is meaningful.
  • Establish the basis for grouping In the present invention, first try different grouping standards, combine the starting dose of Gn and the distribution of the predicted low response rate, and try a variety of grouping methods from small to large grouping intervals. It was found that the interaction of the grouping methods in the present invention is meaningful.
  • the grouping module calculates the predicted probability of a subject's LOR based on the prediction model of the above formula 1, and classifies the calculated probability according to the pre-stored grouping basis.
  • the predicted probability of low response is divided into the following four categories, namely:
  • the predicted probability of LOR (p) is ⁇ 5%
  • the sample size is estimated first, and the total sample size should be> 553, and all couples try to be pregnant for at least 12 months.
  • a total of 561 couples were included in the three reproductive medical centers to conduct the study according to the following inclusion and exclusion criteria, that is, 561 couples that met the following inclusion and exclusion criteria were selected for subsequent research.
  • Inclusion criteria were: women aged 20 to 45 years, body mass index (BMI) ⁇ 30, six consecutive menstrual cycles of 25 to 45 days, bilateral ovarian morphology was assessed by vaginal ultrasound examination, and previous IVF / ICSI- The number of ET cycles is ⁇ 2.
  • Exclusion criteria hydrosalpinx, AFC unilateral ovaries> 20, polycystic ovary syndrome, other untreated metabolic or endocrine diseases, previous surgery for the ovaries or uterine cavity, intrauterine abnormalities, within 3 months of pregnancy, Genes who smoked, used oral contraceptives or other hormones within the previous two months, had previously undergone radiotherapy or chemotherapy, and received PGD (preimplantation genetic diagnosis) / PGS (preimplantation genetic screening) treatment genes Couple having a diagnosis.
  • Gn i.e. human recombinant FSH
  • the starting dose is based on age, BMI (that is, body mass index, which is a number obtained by dividing weight in kilograms by height in meters squared, which is a standard commonly used in the world to measure human body fat and thin and whether it is healthy), menstruation 2 -4 days to choose from FSH and AFC levels.
  • BMI body mass index
  • menstruation 2 -4 days to choose from FSH and AFC levels.
  • the initial dose of Gn was adjusted based on ultrasound observations and serum E2 levels.
  • GnRH antagonist treatment begins on days 5-7 of the stimulus with a growing follicle diameter of 10-12 mm.
  • hCG When at least 2 dominant follicles (diameter 18 mm in diameter) are visible by ultrasound, hCG of 5000-10000 IU is given to trigger final oocyte maturation. Egg retrieval was performed 36 hours after hCG administration. 1-3 embryos are transferred or cryopreserved. Progesterone support is then provided for the luteal phase.
  • the follicle stimulating hormone (FSH) level at 2-4 days of menstruation refers to the level of follicle stimulating hormone obtained from the venous blood serum samples of the female subject on the second to fourth day of menstruation.
  • the estrogen level (E2) of 2-4 days of menstruation refers to the estrogen level detected from the venous blood serum samples of female subjects on the second to fourth days of menstruation
  • the AMH level of 2-4 days of menstruation refers to The anti-Mullerian hormone levels and LH levels of 2-4 days of menstrual blood measured on venous blood serum samples of female subjects during the second to fourth days of menstruation refer to the second to fourth days of menstruation. Luteinizing hormone levels were measured in venous blood serum samples of female subjects.
  • Serum samples were taken and frozen at -80 ° C. The sealed samples were stored at room temperature (15 to 30 ° C) for no more than 24 hours. Sample collection is done at the hospital where the patient is seen, and immunoassays are performed to avoid multiple freeze-thaw cycles.
  • FSH, LH, E2 and AMH measurements were performed by Access UniCel DxI 800 Chemiluminescence System (Beckman Coulter Inc). The quality control of FSH, LH and E2 is provided by Bio-RAD Laboratories (Lyphochek Immunoassay Plus Control, trilevel). The product number is 370 and the batch number is 40300. AMH quality control is provided by the Beckman AMH kit. For AMH, FSH and LH, the coefficient of variation of the three levels of high, middle and low is controlled to be less than 5%, and for estradiol, the coefficient of variation of the three levels of high, middle and low is controlled to be less than 10%.
  • the variables used for prediction include age, BMI, cause of infertility, AFC count of vaginal B-count in 2-4 days of menstruation, FSH level of 2-4 days of menstruation, AMH level of 2-4 days of menstruation , LH level of 2-4 days of menstruation, and E2 level of 2-4 days of menstruation, and the outcome variable set is low ovarian response (hereinafter also referred to as LOR).
  • LOR low ovarian response
  • low ovarian response is defined as less than 5 (ie, 0-4) oocytes obtained on the day of egg retrieval. Differences between the two groups were tested by t-test, Wilcoxon test, or chi-square test, and appropriate methods were adopted based on the data.
  • a binary logistic regression model is used to select important factors related to LOR.
  • ROC Subject Working Characteristic
  • a total of 561 couples who participated in the GnRH antagonist cycle met the above inclusion and exclusion criteria.
  • the data of these 561 couples was collected, and the collected data was input into SAS software and R software for analysis. And obtain the data in Tables 1 and 2 below.
  • Table 1 shows the basic and clinical characteristics of the above 561 couples related to the oocytes removed.
  • the above software was used to perform multi-factor regression analysis on the above data to determine which factors are independent predictors of LOR after correction of related factors.
  • the results are shown in Table 2. According to the results in Table 2, age, AMH levels of 2-4 days of menstruation, FSH levels of 2-4 days of menstruation, and AFC numbers of 2-4 days of menstruation were significantly related to LOR, and their respective p-values were 0.0056, 0.0044, 0.0195 and 0.0049.
  • age, AMH, FSH, and AFC were converted into binary variables by using the tangent values of the ROC curve. Specifically, the ROC curve is used to determine the cut-off point of age, AMH, FSH, and AFC, and the cut-point value of the cut-off point is determined. The results are shown in Figures 1 to 4, respectively. According to the results of Figures 1 to 4, Find the cut-off values for age, AMH, FSH, and AFC as 35 years old, 0.93, 9.1, and 8, respectively.
  • age, AMH, FSH, and AFC are converted into two categorical variables according to the above criteria.
  • a ROC curve is drawn. As shown in FIG. 5, the area under the ROC curve is 0.883. According to the results in FIG. 5, it can be seen that the model performs well in predicting LOR.
  • the anti-Mullerian hormone concentration in venous blood of a subject's age, 2-4 days of menstruation, and the concentration of follicle stimulating hormone in venous blood of 2-4 days of menstruation was used to calculate the probability of low ovarian response in this subject.
  • the specific method of the above interaction is as follows.
  • the predicted low response probability, the Gn starting dose, and the interaction between the two calculated using Formula One are taken as X, and whether the low response is taken as Y. Multiple logistic regression is performed to achieve a fixed value.
  • the four main factors that affect low ovarian response are the binary variables AFC, AMH, FSH, and age (that is, the predicted low response probability) used in the present invention to see the effect of dose changes on the occurrence of low ovarian response.
  • the clinician can give the subject a corresponding appropriate Gn starting dose according to the grouping.

Abstract

一种预测拮抗剂方案下受试者卵巢低反应概率的系统以及指导促性腺激素起始用药剂量选择的系统。所述用于预测卵巢低反应概率的系统包括：数据采集模块，其用于获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；以及计算卵巢低反应发生概率的模块，其用于将数据采集模块中的获取的信息进行计算从而计算出该受试者发生卵巢低反应的概率，并根据预测的低反应概率给予外源性促性腺激素(Gn)起始剂量建议。

Description

一种预测拮抗剂方案下受试者卵巢低反应概率的系统以及指导促性腺激素起始用药剂量选择的系统 技术领域
本发明涉及一种用于预测在给药拮抗剂方案下受试者卵巢低反应的系统，以及用于指导促性腺激素(Gn)起始剂量范围的系统。
背景技术
在控制性促排卵(COS)过程中，获卵数被认为是IVF-ET(体外授精-胚胎移植)术后能否成功妊娠的有力预测指标。一项发表在权威杂志《Human Reproduction》上的对欧洲40余万人的研究表明，与较低的取卵日获卵数相比，合适的获卵数显著提高活产率。在COS过程中，患者面临的主要问题是获卵数不足，即卵巢低反应，这会导致较高的周期取消率和不良妊娠结局，例如较低的胚胎种植率、妊娠率和活产率。在COS之前预测卵巢反应、并给予合适的外源性促排卵药(Gn)起始剂量是目前临床上公认的避免卵巢低反应的唯一有效方法。世界范围内多种标记物已被应用于评估卵巢低反应，包括年龄，月经2-4天卵泡刺激素(bFSH)水平，窦卵泡计数(AFC)、抗苗勒氏激素(AMH)及月经2-4天雌激素水平(bE2)等。近年来，AMH被认为是预测卵巢储备的最好指标，因此国外开始有团队试图探索AMH与其他指标结合预测卵巢低反应，但是他们的研究是基于促性腺激素释放激素(GnRH)长方案，且主要是针对高加索人种，人群、饮食习惯等均较我国不同。
发明内容
如上所述，判断受试者是否属于卵巢低反应对于临床医生等来说是一个非常重要的工作。此外，为不同患者选择不同起始剂量的促性腺激素(Gn)以便在体外授精胚胎移植(IVF-ET)周期中获得最佳的取卵日获卵数是生殖医生最重要的临床决策。然而，迄今国际上尚无指导临床医生如何针对不同的患者选择合适的Gn起始剂量的标准或指南。也没有合适的手段来帮助临床医生来判断受试者卵巢低反应发生概率的系统。过去，临床医生通常基于女性既往卵巢反应的历史、年龄、BMI、AFC以及月经2-4天血清FSH水平，根据其临床经验来选择Gn的起始剂量。因此，本发明意在提供一种能够准确且方便、快速地预测卵巢低反应的系统，以及意在提供一种能够准确且方便、快速地指导卵巢低反应患者用药的系统。
具体来说，本发明涉及如下内容：
1.一种用于预测受试者发生卵巢低反应概率的系统，其包括：
数据采集模块，其用于获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；
计算卵巢低反应发生概率的模块，其用于将数据采集模块中的获取的上述信息进行计算，从而计算或预测所述受试者发生卵巢低反应的概率。
2.根据项1所述的系统，其中，
所述受试者是在月经周期的第2天或第3天给药外源性促排卵药(Gn)，并在给药外源性促性腺激素(Gn)后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者。
3.根据项1或2所述的系统，其中，
在计算卵巢低反应发生概率的模块中，利用将受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量来计算受试者发生卵巢低反应的概率。
4.根据项1～3中任一项所述的系统，其中，
在计算卵巢低反应发生概率的模块中，利用受试者工作特征(ROC)曲线来检测年龄、 抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用所述二分类变量来计算受试者发生卵巢低反应的概率。
5.根据项1～4中任一项所述的系统，其中，
所述抗缪勒氏管激素(AMH)水平是指女性受试者月经2-4天的静脉血中的抗缪勒氏管激素浓度，所述卵泡刺激素(FSH)水平是指女性受试者月经2-4天的静脉血中的卵泡刺激素浓度，所述窦卵泡计数(AFC)是指阴道B超计数女性受试者月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数。
6.根据项1～5中任一项所述的系统，其中，
所述年龄的切点值为35岁，所述抗缪勒氏管激素(AMH)水平的切点值为0.93ng/ml，所述卵泡刺激素(FSH)水平的切点值为9.1IU/L，以及所述窦卵泡计数(AFC)的切点值为8。
7.根据项1～6中任一项所述的系统，其中，
在计算卵巢低反应发生概率的模块中预先存储有基于现有数据库中受试者的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量拟合而成的用于计算卵巢低反应发生概率的公式。
8.根据项7所述的系统，其中，所述公式为如下公式一：
Figure PCTCN2019088679-appb-000001
其中，i为选自-1.786～-0.499中的任意数值，a为选自0.063-1.342中的任意数值，b为选自-2.542～-1.056中的任意数值，c为选自0.548～1.838中的任意数值，d为选自-2.133～-0.51中的任意数值，其中优选i＝-1.143，优选a＝0.703，优选b＝-1.799，优选c＝1.193，优选d＝-1.322。
9.一种用于指导患者促性腺激素用药剂量确定的系统，其包括：
数据采集模块，其用于获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；
计算卵巢低反应发生概率的模块，其用于将数据采集模块中的获取的上述信息进行计算，从而计算或预测所述受试者发生卵巢低反应的概率；
分组模块，在所述分组模块中预存有分组依据，并且依据该分组依据对计算卵巢低反应发生概率的模块计算出的受试者发生卵巢低反应的概率进行分组；以及
外源性促促性腺激素(Gn)起始剂量的推荐模块，其基于分组模块将受试者所分的组别推荐Gn的起始用药剂量。
10.根据项9所述的系统，其中，
所述受试者是在月经周期的第2天或第3天给药外源性促排卵药(Gn)，并在给药外源性促性腺激素(Gn)后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者。
11.根据项9或10所述的系统，其中，
在所述分组模块中预存的分组依据为利用现有数据库，根据Gn起始剂量与预测的卵巢低反应概率之间的交互作用是否有意义而对发生卵巢低反应概率建立的分组依据。
12.根据项11所述的系统，其中，
在所述分组模块中预存的分组依据为：
受试者发生卵巢低反应的概率<5％；
5％≤受试者发生卵巢低反应的概率<20％；
20％≤受试者发生卵巢低反应的概率<50％；
50％≤受试者发生卵巢低反应的概率。
13.根据项9～12中任一项所述的系统，其中，
在计算卵巢低反应发生概率的模块中，利用将受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量来计算受试者发生卵巢低反应的概率。
14.根据项9～13中任一项所述的系统，其中，
在计算卵巢低反应发生概率的模块中，利用受试者工作特征(ROC)曲线来检测年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用所述二分类变量来计算受试者发生卵巢低反应的概率。
15.根据项9～14中任一项所述的系统，其中，
所述抗缪勒氏管激素(AMH)水平是指女性受试者月经2-4天的静脉血中的抗缪勒氏管激素浓度，所述卵泡刺激素(FSH)水平是指女性受试者月经2-4天的静脉血中的卵泡刺激素浓度，窦卵泡计数(AFC)是指阴道B超计数女性受试者月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数。
16根据项9～15中任一项所述的系统，其中，
所述年龄的切点值为35岁，所述抗缪勒氏管激素(AMH)水平的切点值为0.93ng/ml，所述卵泡刺激素(FSH)水平的切点值为9.1IU/L，以及所述窦卵泡计数(AFC)的切点值为8。
17.根据项9～16中任一项所述的系统，其中，
在计算卵巢低反应发生概率的模块中预先存储有基于现有数据库中受试者的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量拟合而成的用于计算卵巢低反应发生概率的公式。
18.根据项9～17中任一项所述的系统，其中，
所述公式为如下公式一：
Figure PCTCN2019088679-appb-000002
其中，i为选自-1.786～-0.499中的任意数值，a为选自0.063-1.342中的任意数值，b为选自-2.542～-1.056中的任意数值，c为选自0.548～1.838中的任意数值，d为选自-2.133～-0.51中的任意数值，其中优选i＝-1.143，优选a＝0.703，优选b＝-1.799，优选c＝1.193，优选d＝-1.322。
19.一种用于预测受试者发生卵巢低反应概率的方法，其包括：
采集数据步骤，在该步骤中，获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；
计算发生卵巢低反应的概率的步骤，在该步骤中，利用在上述采集数据步骤中获取的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)数据进行计算，从而计算或预测所述受试者发生卵巢低反应的概率。
20.根据项19所述的方法，其中，
所述受试者是在月经周期的第2天或第3天给药外源性促排卵药(Gn)，并在给药外源性促性腺激素(Gn)后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者。
21.根据项19或20所述的方法，其中，
在计算发生卵巢低反应的概率的步骤中，将受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成二分类变量，并利用所述转换成的二分类变量来计算或预测受试者发生卵巢低反应的概率。
22.根据项19～21中任一项所述的方法，其中，
在计算发生卵巢低反应的概率步骤中，利用受试者工作特征(ROC)曲线来检测年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用所述二分类变量来计算受试者发生卵巢低反应的概率。
23.根据项19～22中任一项所述的方法，其中，
所述抗缪勒氏管激素(AMH)水平是指女性受试者月经2-4天的静脉血中的抗缪勒氏管激素浓度，所述卵泡刺激素(FSH)水平是指女性受试者月经2-4天的静脉血中的卵泡刺激素浓度，所述窦卵泡计数(AFC)是指阴道B超计数女性受试者月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数。
24.根据项19～23中任一项所述的方法，其中，
所述年龄的切点值为35岁，所述抗缪勒氏管激素(AMH)水平的切点值为0.93ng/ml，所述卵泡刺激素(FSH)水平的切点值为9.1IU/L，以及所述窦卵泡计数(AFC)的切点值为8。
25.根据项19～24中任一项所述的方法，其中，
在计算卵巢低反应发生概率的步骤中，利用预先的基于现有数据库中受试者的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量拟合而成的用于计算卵巢低反应发生概率的公式来进行计算。
26.根据项18～25中任一项所述的方法，其中，
在计算发生卵巢低反应的概率中，利用如下公式一，根据数据采集步骤中获取的并已经转化为二分类变量的受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据来计算卵巢低反应的概率：
Figure PCTCN2019088679-appb-000003
其中，i为选自-1.786～-0.499中的任意数值，a为选自0.063-1.342中的任意数值，b为选自-2.542～-1.056中的任意数值，c为选自0.548～1.838中的任意数值，d为选自-2.133～-0.51中的任意数值，其中优选i＝-1.143，优选a＝0.703，优选b＝-1.799，优选c＝1.193，优选d＝-1.322。
27.一种用于指导卵巢低反应患者用药的方法，其包括：
采集数据步骤，在该步骤中，获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；
计算发生卵巢低反应的概率，在该步骤中，利用在上述采集数据步骤中获取的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)数据进行计算，从而计算出所述受试者发生卵巢低反应的概率；
依据预存的分组，依据对计算出的所述受试者发生卵巢低反应的概率进行分组；以及根据所述分组情况向受试者推荐Gn的起始用药剂量。
28.根据项27所述的方法，其中，
所述受试者是在月经周期的第2天或第3天给药外源性促排卵药(Gn，并在给药外源性促排卵药(Gn)后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者。
29.根据项27或28所述的方法，其中，
预存的分组依据为利用现有数据库，根据Gn起始剂量与预测的卵巢低反应概率之间的交互作用是否有意义而对发生卵巢低反应概率建立的分组依据。
30.根据项27～29中任一项所述的方法，其中，
预存的分组依据为：
受试者发生卵巢低反应的概率<5％；
5％≤受试者发生卵巢低反应的概率<20％；
20％≤受试者发生卵巢低反应的概率<50％；
50％≤受试者发生卵巢低反应的概率。
31.根据项27～30中任一项所述的方法，其中，
在计算发生卵巢低反应的概率的步骤中，利用将受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量来计算受试者发生卵巢低反应的概率。
32.根据项27～31中任一项所述的方法，其中，
在计算发生卵巢低反应的概率中，利用受试者工作特征(ROC)曲线来检测年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用所述二分类变量来计算受试者发生卵巢低反应的概率。
33.根据项27～31中任一项所述的方法，其中，
所述抗缪勒氏管激素(AMH)水平是指女性受试者月经2-4天的静脉血中的抗缪勒氏管激素浓度，所述卵泡刺激素(FSH)水平是指女性受试者月经2-4天的静脉血中的卵泡刺激素浓度，所述窦卵泡计数(AFC)是指阴道B超计数女性受试者月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数。
34.根据项27～33中任一项所述的方法，其中，
所述年龄的切点值为35岁，所述抗缪勒氏管激素(AMH)水平的切点值为0.93ng/ml，所述卵泡刺激素(FSH)水平的切点值为9.1IU/L，以及所述窦卵泡计数(AFC)的切点值为8。
35.根据项27～34中任一项所述的方法，其中，
在计算卵巢低反应发生概率的步骤中，利用预先的基于现有数据库中受试者的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量拟合而成的用于计算卵巢低反应发生概率的公式来进行计算。
36.根据项27～35中任一项所述的方法，其中，
在计算发生卵巢低反应的概率中，利用如下公式一，根据数据采集步骤中获取的并已经转化为二分类变量的受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据来计算卵巢低反应的概率：
Figure PCTCN2019088679-appb-000004
其中，i为选自-1.786～-0.499中的任意数值，a为选自0.063-1.342中的任意数值，b为选自-2.542～-1.056中的任意数值，c为选自0.548～1.838中的任意数值，d为选自-2.133～-0.51中的任意数值，其中优选i＝-1.143，优选a＝0.703，优选b＝-1.799，优选c＝1.193，优选d＝-1.322。
发明效果
由于在GnRH拮抗剂方案中，血清AMH水平在预测卵巢反应方面表现良好，本发明意在希望获得一个可靠的系统来预测卵巢低反应的系统，以及一个有效的用于指导卵巢低反应患者用药的系统，利用这样的系统根据卵巢低反应的发生概率将受试者归入不同的组别，进而根据该受试者的组别为该受试者指定用药剂量的方案。
具体来说，在本发明中首先可以利用本发明的用于预测受试者发生卵巢低反应的系统来预测受试者发生卵巢低反应的概率。利用本发明的系统，可以预测出卵巢低反应的发生概率，从而可以对卵巢储备进行评估，目前临床对于卵巢储备的评估指标也是预测卵巢低反应的指标，且在做出卵巢储备下降的诊断时临床医生也是用卵巢低反应的诊断标准。因为卵巢储备的定义是指卵巢皮质内的原始卵泡数，原始卵泡数没办法进行无创的评估，只能通过每个月经周期动员的卵泡数进行评估，IVF-ET周期动员的卵泡过少(卵巢低反应)，提示卵巢储备功能下降。因此，预测卵巢低反应除了可以给予一定的用药剂量指导外，还可以用于评估卵巢储备功能以便女性合理安排生育计划。
进一步，利用本发明的用于指导卵巢低反应患者用药的系统，通过首先计算出受试者发生卵巢低反应的概率，然后可以通过分组模块来实现对该受试者发生卵巢低反应的概率进行分类，系统预置的分组标准为：受试者低反应概率<5％组，5％≤受试者发生卵巢低反应的概率<20％的组，20％≤受试者发生卵巢低反应的概率<50％，以及低反应概率大于等于50％组。在分组之后，可以用药剂量的推荐模块来实现对属于不同组别的受试者给出外源性促排卵药(Gn)的推荐起始剂量。
利用本发明的系统可以提示医生应根据病人预测的低反应发生概率由低到高的顺序逐渐增加Gn起始剂量，以实现最好的效价比，从而可以通过较短的治疗周期和较低的治疗成本来改善患者的卵巢反应水平。
本发明的发明人首次在拮抗剂方案中应用月经2-4天AMH水平、年龄、月经2-4天FSH水平及月经2-4天阴道B超计数的AFC四个指标的对卵巢低反应进行预测，并根据预测的卵巢低反应发生概率与外源性促性腺激素(Gn)起始剂量之间的交互作用关系对人群进行分组，给予Gn起始剂量的推荐。
附图说明
通过阅读下文优选的具体实施方式中的详细描述，本申请各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。说明书附图仅用于示出优选实施方式的目的，而并不认为是对本申请的限制。显而易见地，下面描述的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。而且在整个附图中，用相同的附图标记表示相同的部件。
图1针对年龄变量的ROC曲线分析。
图2针对月经2-4天AMH水平变量的ROC曲线分析。
图3针对月经2-4天血清FSH水平变量的ROC曲线分析。
图4针对月经2-4天阴道B超AFC水平变量的ROC曲线分析。
图5预测卵巢低反应(LOR)概率的模型的ROC曲线分析。
图6Gn起始剂量、LOR的预测概率、以及它们之间的交互效应的回归模型图。
具体实施方式
下面将参照附图更详细地描述本发明的具体实施例。虽然附图中显示了本发明的具体实施例，然而应当理解，可以以各种形式实现本发明而不应被这里阐述的实施例所限制。相反，提供这些实施例是为了能够更透彻地理解本发明，并且能够将本发明的范围完整的传达给本领域的技术人员。
需要说明的是，在说明书及权利要求当中使用了某些词汇来指称特定组件。本领域技术人员应可以理解，技术人员可能会用不同名词来称呼同一个组件。本说明书及权利要求并不以名词的差异来作为区分组件的方式，而是以组件在功能上的差异来作为区分 的准则。如在通篇说明书及权利要求当中所提及的“包含”或“包括”为一开放式用语，故应解释成“包含但不限定于”。说明书后续描述为实施本发明的较佳实施方式，然所述描述乃以说明书的一般原则为目的，并非用以限定本发明的范围。本发明的保护范围当视所附权利要求所界定者为准。
在本申请中涉及的几种不孕的因素定义如下。子宫内膜异位症是指有活性的内膜细胞种植在子宫内膜以外的位置而形成的一种女性常见妇科疾病。内膜细胞本该生长在子宫腔内，但由于子宫腔通过输卵管与盆腔相通，因此使得内膜细胞可经由输卵管进入盆腔异位生长。子宫内膜异位症的主要病理变化为异位内膜周期性出血及其周围组织纤维化，形成异位结节，痛经、慢性盆腔痛、月经异常和不孕是其主要症状。病变可以波及所有的盆腔组织和器官，以卵巢、子宫直肠陷凹、宫骶韧带等部位最常见，也可发生于腹腔、胸腔、四肢等处。输卵管性不孕是指，由于输卵管具有运送精子、拾取卵子及把受精卵运送到子宫腔的重要作用，输卵管不通或功能障碍成为女性不孕症的主要原因。造成输卵管不通或功能障碍的原因是急、慢性输卵管炎症。此外，不明原因不孕症被定义为经排卵测试，输卵管通畅和精液分析的测试等标准检测结果显示正常的，但具有反复受孕失败的历史的夫妇。
连续变量：在统计学中，变量按变量值是否连续可分为连续变量与分类变量两种。在一定区间内可以任意取值的变量叫连续变量，其数值是连续不断的，相邻两个数值可作无限分割，即可取无限个数值。例如，生产零件的规格尺寸，人体测量的身高、体重、胸围等为连续变量，其数值只能用测量或计量的方法取得。反之，其数值只能用自然数或整数单位计算的则为离散变量。例如，企业个数，职工人数，设备台数等，只能按计量单位数计数，这种变量的数值一般用计数方法取得。
分类变量是指地理位置、人口统计等方面的变量，其作用是将调查响应者分群。描述变量是描述某一个客户群与其他客户群的区别。大部分分类变量也就是描述变量。分类变量可以分为无序分类变量和有序分类变量两大类。其中，无序分类变量(unordered categorical variable)是指所分类别或属性之间无程度和顺序的差别。其又可分为①二项分类，如性别(男、女)，药物反应(阴性和阳性)等；②多项分类，如血型(O、A、B、AB)，职业(工、农、商、学、兵)等。而有序分类变量(ordinal categorical variable)各类别之间有程度的差别。如尿糖化验结果按－、±、+、++、+++分类；疗效按治愈、显效、好转、无效分类。对于有序分类变量，应先按等级顺序分组，清点各组的观察单位个数，编制有序变量(各等级)的频数表，所得资料称为等级资料。
变量类型不是一成不变的，根据研究目的的需要，各类变量之间可以进行转化。例如血红蛋白量(g/L)原属数值变量，若按血红蛋白正常与偏低分为两类时，可按二项分类资料分析；若按重度贫血、中度贫血、轻度贫血、正常、血红蛋白增高分为五个等级时，可按等级资料分析。有时亦可将分类资料数量化，如可将病人的恶心反应以0、1、2、3表示，则可按数值变量资料(定量资料)分析。
本发明涉及一种用于预测受试者发生卵巢低反应概率的系统，其包括：
数据采集模块，其用于获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；
计算卵巢低反应发生概率的模块，其用于将数据采集模块中的获取的上述信息进行计算，从而计算出所述受试者发生卵巢低反应的概率。
在本发明的系统中，所述受试者是在月经周期的第2天或第3天给药外源性促性腺激素(Gn)，并在给药外源性促性腺激素(Gn)后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者。
在本发明中的卵巢低反应是指在上述在月经周期的第2天或第3天给药外源性促性腺激素(Gn)，并在给药外源性促性腺激素(Gn)后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者的条件下，在获卵日得到低于5个(即0-4个)卵母细胞，预测发生卵巢 低反应的概率是指利用本发明的系统计算出的数据。
具体来说，在月经周期的第2天或第3天开始外源性促性腺激素(Gn)治疗。起始剂量根据年龄、BMI(即身体质量指数，是用体重公斤数除以身高米数平方得出的数字，是目前国际上常用的衡量人体胖瘦程度以及是否健康的一个标准)、月经2-4天FSH和AFC水平来选择。在促排卵期间，Gn起始剂量根据超声观察和血清E2水平来调整。GnRH拮抗剂治疗开始于刺激第5-7天，生长的卵泡直径为10-12mm时。当通过超声可见至少2个优势卵泡(直径≥18mm)时，给予5000-10000IU的hCG以引发最终的卵母细胞成熟。hCG给药36小时后进行取卵。移植1-3个胚胎或进行胚胎冷冻保存。然后提供了黄体期黄体酮支持物。
在一个具体的实施方式中，在本发明所指拮抗剂方案中，外源性促性腺激素(Gn)为外源性人重组卵泡刺激素(rFSH)。
在计算卵巢低反应发生概率的模块中，利用将受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量来计算或预测受试者发生卵巢低反应的概率。
抗缪勒氏管激素(AMH)是一种由卵巢小卵泡的颗粒层细胞所分泌的荷尔蒙，胎儿时期的女宝宝从9个月大便开始制造AMH，卵巢内的小卵泡数量越多，AMH的浓度便越高；反之，当卵泡随着年龄及各种因素逐渐消耗，AMH浓度也会随之降低，越接近更年期，AMH便渐趋于0。
卵泡刺激素(FSH)是垂体前叶嗜碱性细胞分泌的一种激素，成分为糖蛋白，主要作用为促进卵泡成熟。FSH可促进卵泡颗粒层细胞增生分化，并促进整个卵巢长大。而其作用于睾丸曲细精管则可促进精子形成。FSH在人体内呈脉冲式分泌，女性随月经周期而改变。测定血清中FSH对了解垂体内分泌功能，间接了解卵巢的功能状态、评估卵巢储备及卵巢反应性、制定促排卵用药剂量等不孕和内分泌疾病的诊断治疗都有重要的意义。
窦卵泡计数(AFC)是指月经2-4天两个卵巢中直径为2-8mm的所有可见卵泡的个数。AFC可以通过超声波对卵泡测量和计数。
在本发明中抗缪勒氏管激素(AMH)水平是指女性受试者月经2-4天的静脉血血清样本中的抗缪勒氏管激素浓度，卵泡刺激素(FSH)水平是指女性受试者月经2-4天的静脉血血清样本中的卵泡刺激素浓度，窦卵泡计数(AFC)是指阴道B超计数女性受试者月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数。
在计算卵巢低反应发生概率的模块中，利用受试者工作特征(ROC)曲线来检测年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用所述全部的二分类变量来带入上述公式来计算受试者发生卵巢低反应的概率。
虽然在现有技术中，有研究者尝试采用某些上述参数来进行分析，但是通过利用受试者工作特征(ROC)曲线来检测年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用全部的二分类变量来带入上述公式来计算受试者发生卵巢低反应的概率是本发明的发明人意想不到的发现，通过将上述4个变量变换成二分类变量，利用这样的二分类变量来进行数据分析可以更为准确地预测受试者发生卵巢低反应的概率，且模型稳定性更好。通过准确地预测发生卵巢低反应的概率也可以更为有效地实现对受试者的分组，从而更有有效地指导外源性促性腺激素(Gn)的起始用药剂量。
在发明中，年龄的切点值为35岁，抗缪勒氏管激素(AMH)水平的切点值为0.93ng/ml，卵泡刺激素(FSH)水平的切点值为9.1IU/L，以及窦卵泡计数(AFC)的切点值为 8。
在计算卵巢低反应发生概率的模块中预先存储有基于现有数据库中受试者的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量拟合而成的用于计算卵巢低反应发生概率的公式。
在本发明中，现有数据库是指能够获取的正在接受治疗或以前接受治疗满足下述纳入和排除标准的受试者组成的数据库，对于数据库的样本量没有任何约定，当然数据库的样本量越大越好，例如可以是利用100个受试者，200个受试者，300个受试者，优选为400个受试者以上，更优选为500个受试者以上。在一个具体的实施例中，采用的561个样本组成的现有数据库。
上述纳入和排除标准分别为，纳入标准为：年龄在20～45岁之间的女性，体重指数(BMI)≤30，连续六个月经周期为25至45天，通过阴道超声检查评估双侧卵巢形态正常，既往IVF/ICSI-ET周期数≤2。排除标准为：输卵管积水，单侧卵巢AFC>20，多囊卵巢综合征，其他未经治疗的代谢或内分泌疾病，针对卵巢或宫腔的既往手术，宫内异常，妊娠3个月以内，吸烟，在之前的两个月内使用口服避孕药或其它激素，之前经历过放疗或化疗，接受PGD(植入前胚胎遗传学诊断)/PGS(胚胎植入前遗传学筛查)治疗的基因诊断的夫妇。
在选择数据库的样本时，能够纳入数据库使用的受试者需要同时满足上述纳入和排除标准。
计算卵巢低反应发生概率的模块利用如下公式来根据数据采集模块中获取的数据来计算卵巢低反应的概率：
Figure PCTCN2019088679-appb-000005
其中，i为选自-1.786～-0.499中的任意数值，a为选自0.063-1.342中的任意数值，b为选自-2.542～-1.056中的任意数值，c为选自0.548～1.838中的任意数值，d为选自-2.133～-0.51中的任意数值，其中最优选i＝-1.143，最优选a＝0.703，最优选b＝-1.799，最优选c＝1.193，最优选d＝-1.322。
此外，本发明涉及的用于指导卵巢低反应患者用药的系统，除了包括上述数据采集模块和上述计算卵巢低反应发生概率的模块之外，还包括：
分组模块，在所述分组模块中预存有分组依据，并且依据该分组依据对计算卵巢低反应发生概率的模块计算出的受试者发生卵巢低反应的概率进行分组；具体来说其根据预置数据库将人群根据预测的低反应概率分为四组，受试者得到计算的低反应发生率后，会被系统自动分配到相应的组别，以及
外源性促性腺激素(Gn)起始用药剂量的推荐模块，其基于分组模块将受试者所分的组别推荐Gn的起始用药剂量。
上述预存的分组依据为利用现有数据库，根据Gn起始剂量与预测的卵巢低反应概率之间的交互作用是否有意义而对发生卵巢低反应概率建立的分组依据。
也就是说，在本发明中，利用现有数据库中的受试者根据这些受试者的Gn起始剂量与预测的卵巢低反应概率之间的交互作用是否有意义而对发生卵巢低反应概率建立分组依据，在本发明中，首先尝试不同的分组标准，结合Gn起始剂量与预测的低反应发生 率分布情况，按照分组间距从小到大的方式试了多种分组方式，通过多次拟合发现本发明中的分组方式其相互作用是有意义的。
在本发明的一个具体的实施方式汇总，分组模块基于上述公式一的预测模型，计算出某一受试者的LOR的预测概率，并按照预存的分组依据将计算出来的概率进行分类，分组依据是将预测的发生低反应的概率分为如下四类，即：
LOR的预测概率(p)<5％；
5％≤LOR的预测概率(p)<20％；
20％≤LOR的预测概率(p)<50％；
50％≤LOR的预测概率(p)，
并根据分类的结果来控制Gn的起始剂量。
实施例
在实施例中，首先进行样本量估算，总样本量应>553人，所有夫妇均努力尝试怀孕至少12个月。
按照下述纳入和排除标准来三个生殖医学中心共纳入561对夫妇进行该研究，即选择了561对满足下述纳入和排除标准的夫妇用于后续的研究。
纳入标准为：年龄在20～45岁之间的女性，体重指数(BMI)≤30，连续六个月经周期为25至45天，通过阴道超声检查评估双侧卵巢形态正常，既往IVF/ICSI-ET周期数≤2。
排除标准为：输卵管积水，单侧卵巢AFC>20，多囊卵巢综合征，其他未经治疗的代谢或内分泌疾病，针对卵巢或宫腔的既往手术，宫内异常，妊娠3个月以内，吸烟，在之前的两个月内使用口服避孕药或其它激素，之前经历过放疗或化疗，接受PGD(植入前胚胎遗传学诊断)/PGS(胚胎植入前遗传学筛查)治疗的基因诊断的夫妇。
控制性卵巢刺激(COS)治疗
在月经周期的第2天或第3天开始给予Gn(即人重组FSH)治疗。起始剂量根据年龄、BMI(即身体质量指数，是用体重公斤数除以身高米数平方得出的数字，是目前国际上常用的衡量人体胖瘦程度以及是否健康的一个标准)、月经2-4天FSH和AFC水平来选择。在促排卵期间，Gn起始剂量根据超声观察和血清E2水平来调整。GnRH拮抗剂治疗开始于刺激第5-7天，生长的卵泡直径为10-12mm时。当通过超声可见至少2个优势卵泡(直径≥18mm)时，给予5000-10000IU的hCG以引发最终的卵母细胞成熟。hCG给药36小时后进行取卵。移植1-3个胚胎或进行胚胎冷冻保存。然后提供了黄体期黄体酮支持物。
窦卵泡计数测量和内分泌测定
在COS周期期间，所有受试者在月经周期第2-4天进行经阴道超声扫描，通过测量在两个卵巢中直径为2-8mm的所有可见卵泡来进行窦卵泡计数(AFC)。在同一天，为了进行月经2-4天血清AMH，月经2-4天血清FSH，月经2-4天血清LH(促黄体生成素)和月经2-4天血清E2(雌二醇)检测，而进行静脉血液采样。
在本实施例中，月经2-4天时的卵泡刺激素(FSH)水平是指对处于经期第二天～第四天的女性受试者的静脉血血清样本进行检测得到的卵泡刺激素水平。月经2-4天雌激素水平(E2)是指对处于经期第二天～第四天的女性受试者的静脉血血清样本进行检测得到的雌激素水平，月经2-4天AMH水平是指对处于经期第二天～第四天的女性受试者的静脉血血清样本进行检测得到的抗缪勒氏管激素水平、月经2-4天LH水平是指对处于经期第二天～第四天的女性受试者的静脉血血清样本进行检测得到的促黄体生成素水平。
提取血清样品，并在-80℃冷冻。密封的样品被储存在室温(15至30℃)下不超过24小时。样品采集在患者就诊的医院完成，然后进行免疫测定，以避免多次冻融循环。FSH，LH，E2和AMH测量均由Access UniCel DxI 800化学发光体系(Beckman Coulter Inc)来进行。FSH，LH和E2的质量控制是由Bio-RAD Laboratories(Lyphochek Immunoassay Plus Control，trilevel)提供，产品号为370，批号为40300。AMH的质量控制由Beckman AMH 试剂盒提供。对于AMH、FSH和LH，高中低三水平变异系数控制在小于5％，对于雌二醇，高中低三水平变异系数控制在小于10％。
分析方案
在实施例的分析中，用于预测的变量包括年龄、BMI、不孕原因、月经2-4天阴道B超计数的AFC个数、月经2-4天FSH水平、月经2-4天AMH水平、月经2-4天LH水平以及月经2-4天E2水平，设定的结果变量是卵巢低反应(以下，也简称为LOR)。其中，卵巢低反应定义为获卵日得到低于5个(即0-4个)卵母细胞。两组之间的差异通过t检验，Wilcoxon检验或卡方检验进行检验，根据数据的不同采取合适的方法。
首先，使用二元逻辑回归模型来选择与LOR相关的重要因素。为了让模型有更好的适应性，即变换了数据(人群)后仍然可能有较好的实际意义，我们使用ROC(受试者工作特征)曲线的方法对预测LOR的相关四个连续变量指标根据分界点(cut-off point)，进行变量变化，将连续变量变成了分类变量，下文中还将详细地描述该过程。然后使用逻辑回归利用二分类变量来重新建立预测模型，并计算LOR的预测概率。
如上所述，在本实施例中，共有561对参加GnRH拮抗剂周期夫妇符合上述纳入和排除标准，收集了这561对夫妇的数据，将收集到的数据输入SAS软件和R软件中，进行分析，并获得下表1和2的数据。表1显示了上述561对夫妇与取出的卵母细胞相关的基本和临床特征。
表1.与取出的卵母细胞结果相关的患者临床和生物数据
Figure PCTCN2019088679-appb-000006
Figure PCTCN2019088679-appb-000007
中位数，四分位数
根据表1中的结果可以看出，BMI、月经2-4天LH水平和月经2-4天E2变量没有显著差异。另一方面，年龄、不孕原因(对不同不孕原因分类进行计数，应用卡方检验，计算是否有统计学意义p<0.001，说明不孕原因对是否为低反应有统计学意义、月经2-4天AMH和FSH水平、AFC水平、Gn起始剂量和总剂量与获得的卵母细胞具有重要的相关性，p值列于表1中。
利用上述软件对以上数据进行多因素回归分析，以确定在校正了相关因素后，哪些因素是影响LOR的独立预测指标，结果如表2所示。根据表2的结果显示年龄、月经2-4天AMH水平、月经2-4天FSH水平和月经2-4天AFC个数与LOR显著相关，其各自的p值分别为0.0056、0.0044、0.0195和0.0049。
表2.多因素分析以用于确定影响LOR的独立预测指标
Figure PCTCN2019088679-appb-000008
进一步为了提供更实际的含义，通过使用ROC曲线的切点值将年龄、AMH、FSH和AFC转换成二分类变量。具体来说，采用ROC曲线确定年龄、AMH、FSH、AFC的分界点，并分别确定该分界点的切点值，其结果分别如图1到图4所示，根据图1到图4的结果，找到年龄、AMH、FSH、AFC的切点值分别为35岁、0.93、9.1、8。可以确认四个指标的结果分别依次如下年龄，AMH，FSH和AFC的切点值分别为35岁，0.93ng/ml，9.1IU/L和8，由此将年龄分为<＝35和>35，AMH分为<＝0.93和>0.93，FSH分为<＝9.1和>9.1，AFC分为<＝8和>8，从而依据上述标准将年龄、AMH、FSH和AFC转换成二分类变量。
对如上所述新产生的四个二分类变量，将其视为X，对于是否为LOR视为Y，做预测是否卵巢低反应的多因素分析，建立的模型参数估计值如下表3所示。
表3 利用多因素分析建立模型的参数值
Figure PCTCN2019088679-appb-000009
Figure PCTCN2019088679-appb-000010
根据表3的数据最终建立的模型logistic预测模型为：
Figure PCTCN2019088679-appb-000011
根据表3的数据可以确定，i的范围为-1.786～-0.499，最优选i＝-1.143，
a的范围为0.063-1.342，最优选a＝0.703，b的范围为-2.542～-1.056，最优选b＝-1.799，c的范围为0.548～1.838，最优选c＝1.193，d的范围为-2.133～-0.51，最优选d＝-1.322。
进一步，按照预测模型，画出ROC曲线，如图5所示，其ROC曲线下的面积为0.883，根据图5的结果可以看出该模型在预测LOR方面表现出色。
由此，根据上述公式一可以基于对某一受试者的年龄、月经2-4天的静脉血中的抗缪勒氏管激素浓度，月经2-4天的静脉血中的卵泡刺激素浓度，月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数来计算这个受试者卵巢低反应的概率。
根据计算出的预测的低反应概率对人群进行分组，以期做到把具有相似卵巢反应性的人群分为一组，给予一定范围的剂量建议。
在本发明中尝试了不同的分组方法，并随后通过交互作用进行检验发现只有按照预测低反应概率<5％,5％≤低反应概率<20％；20％≤低反应概率<50％；50％≤低反应概率分成四组的时候，预测的低反应概率与Gn起始剂量的交互作用才有意义(p＝0.0324)。
上述交互作用的具体做法是这样的，将利用公式一计算的预测的低反应概率、Gn起始剂量以及两者的交互作用作为X，是否低反应作为Y，进行多元逻辑回归，从而实现固定了影响卵巢低反应的四个主要因素即本发明中使用的二分类变量AFC，AMH，FSH以及年龄(即预测的低反应概率)看剂量变化对是否发生卵巢低反应的影响。交互作用结果显示，将人群分为低反应概率<5％,5％≤低反应概率<20％；20％≤低反应概率<50％；50％≤低反应概率这四组时，交互作用模型是有意义的P＝0.0324，如交互作用图，即图6可见，<5％，20％≤低反应概率<50％，50％≤低反应概率这三组，LOR发生率随着剂量增加而减少，而在5％≤低反应概率<20％组，LOR发生率随着剂量的增加而增加，原因可能是改组病人由于大夫错误判断了其卵巢储备，给予了较大的剂量，反而导致了卵巢低反应。为了避免卵巢低反应，四组人群的建议剂量采用各组非卵巢低反应者的四分位数。
如上所述，通过本发明方法将计算的受试者发生低反应的概率进行分组之后，临床医生可以根据分组情况给予受试者相应合适的Gn起始剂量。
尽管以上结合附图对本发明的实施方案进行了描述，但本发明并不局限于上述的具体实施方案和应用领域，上述的具体实施方案仅仅是示意性的、指导性的，而不是限制性的。本领域的普通技术人员在本说明书的启示下和在不脱离本发明权利要求所保护的范围的情况下，还可以做出很多种的形式，这些均属于本发明保护之列。

Claims (18)

  1. 一种用于预测受试者发生卵巢低反应概率的系统，其包括：
    数据采集模块，其用于获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；
    计算卵巢低反应发生概率的模块，其用于将数据采集模块中的获取的上述信息进行计算，从而计算出所述受试者发生卵巢低反应的概率。
  2. 根据权利要求1所述的系统，其中，所述受试者是在月经周期的第2天或第3天给药外源性促性腺激素(Gn)，并在给药外源性促性腺激素(Gn)后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者。
  3. 根据权利要求1所述的系统，其中，在计算卵巢低反应发生概率的模块中，利用将受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量来计算受试者发生卵巢低反应的概率。
  4. 根据权利要求3所述的系统，其中，在计算卵巢低反应发生概率的模块中，利用受试者工作特征(ROC)曲线来检测年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用所述二分类变量来计算受试者发生卵巢低反应的概率。
  5. 根据权利要求4所述的系统，其中，所述抗缪勒氏管激素(AMH)水平是指女性受试者月经2-4天的静脉血中的抗缪勒氏管激素浓度，所述卵泡刺激素(FSH)水平是指女性受试者月经2-4天的静脉血中的卵泡刺激素浓度，所述窦卵泡计数(AFC)是指阴道B超计数女性受试者月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数。
  6. 根据权利要求4或5所述的系统，其中，所述年龄的切点值为35岁，所述抗缪勒氏管激素(AMH)水平的切点值为0.93ng/ml，所述卵泡刺激素(FSH)水平的切点值为9.1IU/L，以及所述窦卵泡计数(AFC)的切点值为8。
  7. 根据权利要求1～6中任一项所述的系统，其中，在计算卵巢低反应发生概率的模块中，预先存储有基于现有数据库中受试者的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量拟合而成的用于计算卵巢低反应发生概率的公式。
  8. 根据权利要求7所述的系统，其中，所述公式为如下公式一：
    Figure PCTCN2019088679-appb-100001
    其中，i为选自-1.786～-0.499中的任意数值，a为选自0.063-1.342中的任意数值，b为选自-2.542～-1.056中的任意数值，c为选自0.548～1.838中的任意数值，d为选自-2.133～-0.51中的任意数值，其中优选i＝-1.143，优选a＝0.703，优选b＝-1.799，优选c＝1.193，优选d＝-1.322。
  9. 一种用于指导患者外源性促性腺激素(Gn)起始用药剂量的系统，其包括：
    数据采集模块，其用于获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；
    计算卵巢低反应发生概率的模块，其用于将数据采集模块中的获取的上述信息进行计算，从而计算出所述受试者发生卵巢低反应的概率；
    分组模块，在所述分组模块中预存有分组依据，并且依据该分组依据对计算卵巢低反应发生概率的模块计算出的受试者发生卵巢低反应的概率进行分组；以及
    外源性促性腺激素(Gn)起始用药剂量的推荐模块，其基于分组模块将受试者所分的组别推荐Gn的起始用药剂量。
  10. 根据权利要求9所述的系统，其中，
    所述受试者是在月经周期的第2天或第3天给药外源性促排卵药(Gn)，并在给药外源性促排卵药后的5～7天给药促性腺激素释放激素(GnRH)的拮抗剂的受试者。
  11. 根据权利要求9所述的系统，其中，
    在所述分组模块中预存的分组依据为利用现有数据，根据外源性促排卵药(Gn)起始剂量与预测的卵巢低反应概率之间的交互作用是否有意义而对发生卵巢低反应概率建立的分组依据。
  12. 根据权利要求11所述的系统，其中，在所述分组模块中预存的分组依据为：
    受试者发生卵巢低反应的概率<5％；
    5％≤受试者发生卵巢低反应的概率<20％；
    20％≤受试者发生卵巢低反应的概率<50％；
    受试者发生卵巢低反应的概率≥50％。
  13. 根据权利要求10所述的系统，其中，在计算卵巢低反应发生概率的模块中，利用将受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量来计算受试者发生卵巢低反应的概率。
  14. 根据权利要求13所述的系统，其中，在计算卵巢低反应发生概率的模块中，利用受试者工作特征(ROC)曲线来检测年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的分界点，并根据该分界点的切点值来将年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)转换成二分类变量，从而利用所述二分类变量来计算受试者发生卵巢低反应的概率。
  15. 根据权利要求14所述的系统，其中，所述抗缪勒氏管激素(AMH)水平是指女性受试者月经2-4天的静脉血中的抗缪勒氏管激素浓度，所述卵泡刺激素(FSH)水平是指女性受试者月经2-4天的静脉血中的卵泡刺激素浓度，窦卵泡计数(AFC)是指阴道B超计数女性受试者月经2-4天时的两个卵巢中直径为2-8mm的所有可见卵泡的个数。
  16. 根据权利要求14或15所述的系统，其中，所述年龄的切点值为35岁，所述抗缪勒氏管激素(AMH)水平的切点值为0.93ng/ml，所述卵泡刺激素(FSH)水平的切点值为9.1IU/L，以及所述窦卵泡计数(AFC)的切点值为8。
  17. 根据权利要求9～16中任一项所述的系统，其中，在计算卵巢低反应发生概率的模块中预先存储有基于现有数据库中受试者的受试者年龄、受试者抗缪勒氏管激素(AMH)水平、受试者卵泡刺激素(FSH)水平、受试者窦卵泡计数(AFC)的数据转换成的二分类变量拟合而成的用于计算卵巢低反应发生概率的公式。
  18. 根据权利要求17所述的系统，其中，
    所述公式为如下公式一：
    Figure PCTCN2019088679-appb-100002
    其中，i为选自-1.786～-0.499中的任意数值，a为选自0.063-1.342中的任意数值，b为选自-2.542～-1.056中的任意数值，c为选自0.548～1.838中的任意数值，d为选自-2.133～-0.51中的任意数值，其中优选i＝-1.143，优选a＝0.703，优选b＝-1.799，优选c＝1.193，优选d＝-1.322。
PCT/CN2019/088679 2018-06-05 2019-05-28 一种预测拮抗剂方案下受试者卵巢低反应概率的系统以及指导促性腺激素起始用药剂量选择的系统 WO2019233308A1 (zh)

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