WO2023103189A1 - 预测受试者卵巢刺激过程中获得的卵母细胞数量的系统和方法 - Google Patents

预测受试者卵巢刺激过程中获得的卵母细胞数量的系统和方法 Download PDF

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WO2023103189A1
WO2023103189A1 PCT/CN2022/078998 CN2022078998W WO2023103189A1 WO 2023103189 A1 WO2023103189 A1 WO 2023103189A1 CN 2022078998 W CN2022078998 W CN 2022078998W WO 2023103189 A1 WO2023103189 A1 WO 2023103189A1
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basic
data
inhibin
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French (fr)
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李蓉
徐慧玉
乔杰
冯国双
韩勇
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北京大学第三医院（北京大学第三临床医学院）
杭州青果医疗科技有限责任公司
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    • G—PHYSICS
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    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
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    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
    • 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
    • G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/60—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for patient-specific data, e.g. for electronic patient records
    • 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
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients

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  • the present invention relates to a system and method for predicting the number of oocytes obtained during ovarian stimulation in subjects receiving standard ovulation induction therapy (non-minimal stimulation).
  • NROs The number of retrieved oocytes (NROs) is considered a strong surrogate prognostic marker of successful pregnancy in women undergoing controlled ovarian stimulation (COS) and IVF/ICSI cycles.
  • COS controlled ovarian stimulation
  • Optimal NROs help to increase the live birth rate (Live-birth-rate, LBR).
  • the inventors of the present application tried to combine the basic indicators and activation indicators, and according to the changes in the indicators during the ovulation induction process, establish a reliable mathematical model for predicting the number of eggs retrieved in the GnRH antagonist program during the ovulation induction process, so that Adjustment of dosage of ovulation-stimulating drugs during ovulation induction.
  • the technical solution developed by the inventors of the present application is beneficial to the number of retrieved eggs and the pregnancy outcome of women receiving assisted reproductive technology treatment.
  • the purpose of the present invention is to provide an effective system, which can be used to predict the number of mature oocytes obtained if a subject receives standard ovulation induction treatment, and can be combined with other systems to better guide ovulation induction in the future Choice of regimen and dose of recombinant FSH.
  • the present invention explores a reliable system to predict NROs in regimens receiving standard ovulation induction therapy (ie, ovulation induction therapy with sufficient rFSH, rather than minimal stimulation). Since hormone levels in a GnRH antagonist regimen are virtually any human's essential hormone levels, the system of the present invention may have important implications for pre-COS assessment and clinical counseling during ovarian stimulation in the general population. Pregnancy outcomes for NROs and women undergoing assisted reproductive technology (ART) treatment are beneficial using the systems or methods of the present invention.
  • ART assisted reproductive technology
  • NROs mature oocytes
  • the present invention relates to the following contents:
  • a system for predicting the number of mature oocytes in a subject comprising:
  • Data acquisition module which is used to obtain the subject's age, basal anti-Müllerian hormone (AMH) level, basal follicle stimulating hormone (FSH) level or basal antral follicle count (AFC), inhibin B level dynamic changes ( ⁇ INHB/difference of inhibin B between day 6 and day 2 of menstruation in an ovulation induction cycle) data; and
  • the calculation module for the number of mature oocytes is used for calculating the above-mentioned data obtained in the data acquisition module, so as to calculate the number of mature oocytes (NROs) obtained by the subject in the ovulation induction cycle.
  • the subject is a subject who will receive standard (sufficient stimulation rather than minimal stimulation) ovulation induction treatment, and the number of mature oocytes of the subject is the ovarian stimulation process after the subject accepts ovulation induction treatment
  • the number of mature oocytes with a diameter of more than 18 mm obtained from the
  • AMD basal anti-Müllerian hormone
  • FSH basal follicle-stimulating hormone
  • AFC basic antral follicle count
  • ⁇ INHB inhibin B level dynamic change
  • the collected basal anti-Mullerian hormone (AMH) level refers to the anti-Mullerian hormone concentration in the venous blood of the subject at any point in the menstrual period before ovulation induction treatment.
  • the collected basal follicle-stimulating hormone (FSH) level refers to the concentration of FSH in the venous blood of female subjects on the second day of menstruation before ovulation induction treatment.
  • the collected basic antral follicle count refers to the number of all visible follicles with a diameter of 2-10mm in the two ovaries of the female subject on the second day of menstruation counted by vaginal B-ultrasound.
  • the collected dynamic change of inhibin B level refers to the dynamic change of inhibin B level ( ⁇ INHB) in the early stage of ovulation induction treatment, preferably for female subjects receiving GnRH antagonist regimen for ovulation induction treatment cycle menstruation
  • ⁇ INHB the dynamic change of inhibin B level
  • the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH ) level or basal antral follicle count (AFC), inhibin B level dynamic change ( ⁇ INHB) data fitting formula used to predict the number of mature oocytes (NROs) of the subject is accepted in the existing database
  • the formula can utilize the subject's age data collected by the data collection module, the subject's basic anti-Müllerian hormone (AMH) level data, the subject's basic follicle stimulating hormone (FSH) level data or the basic Antral follicle count (AFC) data and subject's dynamic change in inhibin B level ( ⁇ INHB) data were used to calculate the number of mature oocytes (NROs) obtained from the subject.
  • AMH basic anti-Müllerian hormone
  • FSH basic follicle stimulating hormone
  • AFC Antral follicle count
  • ⁇ INHB subject's dynamic change in inhibin B level
  • the formula is the following formula one:
  • a is selected from any value in the range of 0.0250603 to 1.1726555, preferably 0.5988579;
  • b is any value selected from -0.021215 to -0.000214, preferably -0.010715;
  • c is selected from any value in -0.031133 ⁇ 0.0043087, preferably -0.013412;
  • d is selected from any value in the range of 0.151584 to 0.2904983, preferably 0.2210412;
  • f is selected from any value in the range of 0.2445264 to 0.3871042, preferably 0.3158153.
  • g is selected from any value from -0.447201 to 0.9161863, preferably 0.2344927;
  • h is selected from any value in the range of -0.017165 to 0.0039328, preferably -0.006616;
  • i is selected from any value in the range of 0.1318094 to 0.3113979, preferably 0.2216036;
  • j is selected from any value in the range of 0.1901643 to 0.3850919, preferably 0.2876281;
  • k is selected from any value in the range of 0.0541966 to 0.2338079, preferably 0.1440023.
  • a method for predicting the number of mature oocytes in a subject comprising:
  • a data collection step which obtains the subject's age, basal anti-Müllerian hormone (AMH) level, basal follicle stimulating hormone (FSH) level or basal antral follicle count (AFC), inhibin B level dynamic change ( ⁇ INHB) data; and
  • the step of calculating the number of mature oocytes which calculates the above-mentioned data obtained in the data collection step, so as to calculate the number of mature oocytes (NROs) obtained from the subject.
  • the subject is a subject who will receive standard ovulation induction treatment, and the number of mature oocytes of the subject is that the diameter of follicles obtained during ovarian stimulation after the subject receives ovulation induction treatment is greater than 18 mm number of mature oocytes.
  • the age In the step of calculating the number of mature oocytes, the age, basic anti-Müllerian hormone (AMH) level, basic follicle stimulating hormone (FSH ) level or basic antral follicle count (AFC), inhibin B level dynamic change ( ⁇ INHB) data fitting formula used to calculate the number of mature oocytes (NROs) of the subject.
  • AMH basic anti-Müllerian hormone
  • FSH basic follicle stimulating hormone
  • AFC basic antral follicle count
  • ⁇ INHB inhibin B level dynamic change
  • the collected basal anti-Müllerian hormone (AMH) level refers to the concentration of anti-Mullerian hormone in the venous blood of the subject at any point in the menstrual period before ovulation induction treatment.
  • the collected basal follicle-stimulating hormone (FSH) level refers to the concentration of FSH in the venous blood of female subjects on the second day of menstruation before ovulation induction treatment.
  • the collected basic antral follicle count refers to the number of all visible follicles with a diameter of 2-10mm in the two ovaries of the female subject on the second day of menstruation counted by vaginal B-ultrasound.
  • the collected dynamic change of inhibin B level refers to the dynamic change of inhibin B level ( ⁇ INHB) in the early stage of ovulation induction treatment, preferably for female subjects receiving GnRH antagonist regimen for ovulation induction treatment for ovulation induction.
  • the age, basic anti-Müllerian hormone (AMH) level, basic follicle stimulating hormone (FSH ) level or basal antral follicle count (AFC), inhibin B level dynamic change ( ⁇ INHB) data fitting formula used to predict the number of mature oocytes (NROs) of the subject is accepted in the existing database
  • the formula can utilize the subject's age data collected in the data collection step, the subject's basic anti-Müllerian hormone (AMH) level data, the subject's basic follicle stimulating hormone (FSH) level data or the basic Antral follicle count (AFC) data and subject's dynamic change in inhibin B level ( ⁇ INHB) data were used to calculate the number of mature oocytes (NROs) obtained from the subject.
  • AMH basic anti-Müllerian hormone
  • FSH basic follicle stimulating hormone
  • AFC Antral follicle count
  • ⁇ INHB subject's dynamic change in inhibin B level
  • the formula is the following formula one:
  • a is selected from any value in the range of 0.0250603 to 1.1726555, preferably 0.5988579;
  • b is any value selected from -0.021215 to -0.000214, preferably -0.010715;
  • c is selected from any value in -0.031133 ⁇ 0.0043087, preferably -0.013412;
  • d is selected from any value in the range of 0.151584 to 0.2904983, preferably 0.2210412;
  • f is selected from any value in the range of 0.2445264 to 0.3871042, preferably 0.3158153.
  • g is selected from any value from -0.447201 to 0.9161863, preferably 0.2344927;
  • h is selected from any value in the range of -0.017165 to 0.0039328, preferably -0.006616;
  • i is selected from any value in the range of 0.1318094 to 0.3113979, preferably 0.2216036;
  • j is selected from any value in the range of 0.1901643 to 0.3850919, preferably 0.2876281;
  • k is selected from any value in the range of 0.0541966 to 0.2338079, preferably 0.1440023.
  • the system and method of the present invention can more accurately predict the number of mature oocytes obtained during ovarian stimulation if the subject receives standard GnRH antagonist regimen for ovulation induction.
  • the system and method of the present invention use the dynamic change of inhibin B level as an evaluation index, which replaces the AFC index with many defects in the prior art, and achieves a better prediction effect.
  • the adjustment of the drug dose during the ovulation induction process is mainly based on the prediction of the number of retrieved eggs.
  • the method or system involved in this application can be used in the ovulation induction process (such as the sixth day of the menstrual cycle of the ovulation induction cycle) to predict the number of eggs obtained according to the changes in the indicators after medication. The number of eggs, so as to adjust the dose of ovulation-stimulating drugs.
  • Fig. 1 is the distribution chart of the fitting outcome variable of the first model and the second model
  • Figure 2 is the prediction effect of the first model in the training set
  • Figure 3 is the prediction effect of the first model in the verification set
  • Figure 4 is the prediction effect of the second model in the training set
  • Figure 5 is the prediction effect of the second model in the validation set.
  • variable types In statistics, variable types can be divided into quantitative variables and qualitative variables (also called categorical variables).
  • Quantitative variables are variables used to describe the quantity and number of things, and can be divided into continuous type and discrete type.
  • a continuous variable refers to a variable that can take any value within a certain interval, and its value is continuous and can have a decimal point.
  • blood pressure, blood sugar, anthropometric height, weight, chest circumference, etc. are continuous variables whose values can only be obtained by measurement or measurement.
  • Discrete variables refer to variables whose values can only be natural numbers or integer units. For example, the pain score, the number of metastatic lesions, the number of retrieved eggs, etc., can only be positive numbers, and decimal points cannot be taken. The values of such variables are generally obtained by counting methods.
  • Variable types are not static, and various types of variables can be transformed according to the needs of the research purpose.
  • the amount of hemoglobin (g/L) is originally a numerical variable. If it is divided into two categories according to normal and low hemoglobin, it can be analyzed according to binomial classification data; When the height increase is divided into five grades, it can be analyzed according to grade data.
  • the categorical data can also be quantified. For example, if the patient's nausea reaction can be represented by 0, 1, 2, 3, it can be analyzed according to the numerical variable data (quantitative data).
  • the Poisson distribution is a discrete probability distribution commonly seen in statistics and probability.
  • the Poisson distribution is suitable for describing the number of random events occurring per unit time (or space). For example, the number of disease cases in a fixed space and time, the number of recurrences of a disease, the number of metastatic sites of a certain lesion, the number of times a patient vomits, and so on.
  • the negative binomial distribution is a discrete probability distribution in statistics.
  • the negative binomial distribution satisfies the following conditions: the experiment consists of a series of independent experiments, each experiment has two outcomes of success and failure, the probability of success is constant, and the experiment lasts until r times of success, where r is a positive integer.
  • the negative binomial distribution is similar to the Poisson distribution, and can also be used to describe the relative frequency of a rare event in a certain unit of time and space. The difference between it and the Poisson distribution is that the Poisson distribution can only be used to describe independent events, while the negative binomial distribution is often used to describe aggregate events, such as the distribution of snails in the soil, the distribution of an infectious disease, etc. Usually, if the count data finds that the mean is greater than the variance, the Poisson distribution often does not fit well, and the negative binomial distribution can be considered.
  • anti-Müllerian hormone refers to a hormone secreted by the granulosa cells of ovarian small follicles.
  • Female babies begin to produce AMH during the fetal period. The more small follicles in the ovary, the more AMH Conversely, when follicles are gradually consumed with age and various factors, the concentration of AMH will also decrease, and the closer to menopause, AMH will gradually tend to 0.
  • FSH follicle-stimulating hormone
  • Basophilic cells of the anterior pituitary gland Its component is glycoprotein, and its main function is to promote follicle maturation.
  • FSH can promote the proliferation and differentiation of follicular granulosa cells, and promote the growth of the entire ovary. And its effect on the seminiferous tubules of the testis can promote sperm formation.
  • FSH is secreted in pulses in the human body, and women change with the menstrual cycle.
  • Determination of FSH in serum is of great significance to the diagnosis and treatment of infertility and endocrine diseases such as understanding pituitary endocrine function, indirectly understanding ovarian function status, evaluating ovarian reserve and ovarian responsiveness, and formulating ovulation-stimulating drug dosage.
  • Inhibin B participates in the selection of follicles in the normal menstrual cycle through endocrine and paracrine effects, and promotes the growth of follicles.
  • One of the actions of inhibin B is to downregulate FSH secretion during the metaphase of the natural menstrual cycle. It also exerts a paracrine effect, stimulating theca cells to produce androgens and LH.
  • Inhibin B secretion peaks in the early follicles, which are 10-12 mm in diameter.
  • Day 5 (early follicular phase) inhibin B has been shown to be a superior marker of poor ovarian response and live birth compared to basal markers.
  • Inhibin B is produced primarily by FSH-sensitive follicles, and administration of exogenous FSH results in its increase in growing follicles. Consistent with this, the inventors of the present application found that the dynamic change of inhibin B level ( ⁇ INHB), that is, the difference between the inhibin B concentration on the 6th day of the ovulation induction cycle and the inhibin B concentration on the 2nd day of menstruation, is the best indicator for predicting the number of eggs retrieved things.
  • ⁇ INHB dynamic change of inhibin B level
  • BMI is an important standard commonly used in the world to measure the degree of obesity and health of the human body, and it is mainly used for statistical analysis.
  • the absolute value of body weight cannot be used to judge the degree of obesity, which is naturally related to height. Therefore, BMI obtains relatively objective parameters through the two values of body weight and height, and uses the range of this parameter to measure body mass.
  • BMI weight/height squared (international unit kg/m 2 ).
  • antral follicle count refers to the number of all visible follicles with a diameter of 2-10 mm in both ovaries on day 2-4 of menstruation.
  • AFC can measure and count follicles by ultrasound.
  • Luteinizing hormone is a glycoprotein gonadotropin secreted by pituitary cells, which can promote the conversion of cholesterol into sex hormones in gonad cells.
  • FSH follicle-stimulating hormone
  • LH prompts the Leydig cells to synthesize and release testosterone.
  • the LH level refers to the LH concentration in the venous blood serum samples of the female subject menstrual 2-4 days.
  • Basal E2 levels refer to levels of estradiol, a steroidal estrogen. There are two types of ⁇ and ⁇ , and the ⁇ type has a strong physiological effect. It has a strong sex hormone effect, so it is thought that it or its esters are actually the most important sex hormones secreted by the ovaries.
  • the detection base estradiol level is the estradiol concentration in the venous blood serum samples of female subjects menstrual 2-4 days.
  • the inventor team of the present application has previously developed a system and method for predicting the number of eggs retrieved in ovulation induction therapy by using the basic ovarian reserve index (the index before ovulation induction therapy). This system is very important for the selection of the initial dose of ovulation induction therapy. However, the response of the same basic ovarian reserve state to ovarian stimulation drugs (recombinant FSH) is also quite different.
  • the present invention relates to a method of establishing a model using basic ovarian reserve indicators combined with ovarian reserve indicators activated early in ovarian stimulation to predict the ovaries obtained during ovarian stimulation when subjects receive standard GnRH antagonist regimens for ovulation induction treatment.
  • a system for the number of oocytes which includes: a data collection module, which is used to obtain the subjects' basic anti-Müllerian hormone (AMH) level, basic follicle-stimulating hormone (FSH) level, and dynamic changes in the early level of inhibin B ( ⁇ INHB) data (i.e.
  • the subject described in this application is a subject who will receive standard GnRH antagonist regimen ovulation induction treatment, and the number of mature oocytes of the subject is obtained during ovarian stimulation after the subject receives ovulation induction treatment The number of mature oocytes with follicles larger than 18 mm in diameter.
  • human recombinant FSH human recombinant FSH (human rFSH) (for example, Gonal-F alfa [Merck Serono, Germany], Puregon beta [MSD, USA], Urofollitropin [Livzon Pharmaceutical Group Inc., China] or Menotrophins[Livzon Pharmaceutical]Group Inc., China]) started administration on the second day of the menstrual cycle.
  • human rFSH was selected based on age, basal AMH level, basal FSH level, basal AFC level, and BMI.
  • the dose of rFSH was further adjusted according to the size and number of growing follicles observed by ultrasound and the monitoring of serum E2 levels during ovarian stimulation.
  • GnRH antagonist therapy was started when the growing follicles reached a diameter of 10-12 mm.
  • hCG Chogonadotropin alfa, Merck Serono
  • Oocyte recovery was performed 36-38 hours after hCG administration. Transfer of one or two embryos or embryo cryopreservation. Subjects were then provided with luteal phase progesterone support (progesterone vaginal gel, Merck Serono).
  • the systems and methods involved in the present application are directed to subjects receiving ovulation induction treatment with standard GnRH antagonist regimens as described above.
  • the present application relates to a system for predicting the number of oocytes obtained during ovarian stimulation of a subject, which includes: a data acquisition module, which is used to acquire the subject's basal anti-Müllerian hormone (AMH) level , the data of the basic follicle stimulating hormone (FSH) level, and the dynamic change of the inhibin B level ( ⁇ INHB); and a module for predicting the number of mature oocytes obtained during ovarian stimulation, which is used for the above-mentioned acquisition in the data acquisition module Data were calculated to calculate the subject's number of mature oocytes retrieved (NROs).
  • AMH basal anti-Müllerian hormone
  • FSH basic follicle stimulating hormone
  • ⁇ INHB dynamic change of the inhibin B level
  • the inventors of this application finally confirmed the subject's age, basal anti-Mullerian hormone (AMH) level, basal follicle stimulating hormone (FSH) level or dual
  • AFC lateral antral follicle count
  • ⁇ INHB inhibin B level dynamic change
  • the data collection module there is no limitation on the data collection module, as long as it can be used to obtain the subject's age, basal anti-Müllerian hormone (AMH) level, basal follicle stimulating hormone (FSH) level, and dynamic changes in inhibin B level ( ⁇ INHB) data.
  • AMH basal anti-Müllerian hormone
  • FSH basal follicle stimulating hormone
  • ⁇ INHB dynamic changes in inhibin B level
  • the basic anti-Mullerian hormone (AMH) level acquired by the data acquisition module refers to the concentration of anti-Mullerian hormone in the venous blood of a female subject at any point in the menstrual period
  • the data acquisition module acquires
  • the basal follicle-stimulating hormone (FSH) level refers to the follicle-stimulating hormone concentration in the venous blood of the female subject on the second day of menstruation
  • the basic antral follicle count (AFC) obtained by the data acquisition module refers to the vaginal B-ultrasound count female
  • the dynamic change of inhibin B level ( ⁇ INHB) obtained by the data acquisition module refers to the ovulation induction cycle of the female subject
  • the above-mentioned data obtained in the data acquisition module are calculated by using the calculation module of the number of mature oocytes, so as to calculate the number of mature oocytes (NROs) of the subject.
  • NROs number of mature oocytes
  • this pre-stored formula is based on the pre-stored age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) ) level or basal antral follicle count (AFC), inhibin B level dynamic change ( ⁇ INHB) data fitting.
  • AH basal anti-Müllerian hormone
  • FSH basal follicle-stimulating hormone
  • AFC basal antral follicle count
  • ⁇ INHB inhibin B level dynamic change
  • this pre-stored formula is the subject's age data collected by the data acquisition module, the subject's basic AMH level data, the subject's basic FSH level data or basic antral follicle count (AFC), And the subject's inhibin B level dynamic change ( ⁇ INHB) data to calculate the formula for the number of mature oocytes (NROs) obtained from the subject.
  • the inventors of the present application constructed a specific formula for predicting NROs.
  • the specific formula is the following formula 1:
  • a is selected from any value in the range of 0.0250603 to 1.1726555, and a is preferably 0.5988579;
  • b is selected from any value from -0.021215 to -0.000214, and b is preferably -0.010715;
  • c is selected from any value from -0.031133 to 0.0043087, and c is preferably -0.013412;
  • d is selected from any value in the range of 0.151584 to 0.2904983, and d is preferably 0.2210412;
  • f is selected from any value in the range of 0.2445264 to 0.3871042, and f is preferably 0.3158153.
  • g is selected from any value in -0.447201 ⁇ 0.9161863, preferably 0.2344927;
  • h is selected from any value in the range of -0.017165 to 0.0039328, preferably -0.006616;
  • i is selected from any value in the range of 0.1318094 to 0.3113979, preferably 0.2216036;
  • j is selected from any value in the range of 0.1901643 to 0.3850919, preferably 0.2876281;
  • k is selected from any value in the range of 0.0541966 to 0.2338079, preferably 0.1440023.
  • the present invention also relates to a method for predicting the number of mature oocytes in a subject, comprising:
  • the data collection step is used to obtain the subject's age, basal anti-Müllerian hormone (AMH) level, basal follicle stimulating hormone (FSH) level or basal antral follicle count (AFC), inhibin B level dynamic change ( ⁇ INHB ) data; and
  • the step of calculating the number of mature oocytes is used to calculate the above data obtained in the data collection step, so as to calculate the number of mature oocytes (NROs) obtained from the subject.
  • the subject is a subject who will receive standard GnRH antagonist regimen ovulation induction treatment, and the number of mature oocytes in the subject is the ovarian stimulation process after the subject accepts ovulation induction treatment The number of mature oocytes obtained in follicles directly larger than 18 mm.
  • the age, basic anti-Müllerian hormone (AMH) level basic anti-Müllerian hormone (AMH) level
  • AMH basic anti-Müllerian hormone
  • NROs number of mature oocytes of a subject is fitted by data fitting of follicle stimulating hormone (FSH) level or basal antral follicle count (AFC) and inhibin B level dynamic change ( ⁇ INHB).
  • FSH follicle stimulating hormone
  • AFC basal antral follicle count
  • ⁇ INHB inhibin B level dynamic change
  • the collected basal anti-Mullerian hormone (AMH) level refers to the anti-Mullerian hormone concentration in the venous blood of the subject at any point in the menstrual period before ovulation induction treatment.
  • the collected basal follicle-stimulating hormone (FSH) level refers to the concentration of FSH in the venous blood of the female subject on the second day of menstruation before ovulation induction treatment.
  • the collected basic antral follicle count refers to the count of all visible follicles with a diameter of 2-10 mm in the two ovaries of the female subject on the second day of menstruation by vaginal B-ultrasound. number.
  • the collected basic antral follicle count refers to the count of all visible follicles with a diameter of 2-10 mm in the two ovaries of the female subject on the second day of menstruation by vaginal B-ultrasound. number.
  • the collected inhibin B level dynamic change refers to the difference between the serum inhibin B concentration and The difference in inhibin B concentration in venous blood of female subjects on the second day of menstrual cycle of ovulation induction cycle.
  • the age, basic anti-Müllerian hormone (AMH) level in the step of calculating the number of mature oocytes, the age, basic anti-Müllerian hormone (AMH) level, basic
  • the formula for predicting the number of mature oocytes (NROs) of the subjects obtained by fitting the data of follicle-stimulating hormone (FSH) level and inhibin B level dynamic change ( ⁇ INHB) is the standard GnRH in the existing database.
  • Data on age, basic anti-Müllerian hormone (AMH) level, basic follicle stimulating hormone (FSH) level or basic antral follicle count (AFC), and dynamic change in inhibin B level ( ⁇ INHB) of patients treated with antagonist regimens for ovulation induction The calculation formula obtained by fitting the negative binomial distribution.
  • the formula can utilize the subject's age data collected by the data collection module, the subject's basic anti-Müllerian hormone (AMH) level data, the subject's basic follicle stimulating hormone (FSH) level data or the basic Antral follicle count (AFC), and subject's inhibin B level dynamic change ( ⁇ INHB) data were used to calculate the number of mature oocytes (NROs) obtained from the subject.
  • AMH basic anti-Müllerian hormone
  • FSH basic follicle stimulating hormone
  • AFC basic Antral follicle count
  • ⁇ INHB subject's inhibin B level dynamic change
  • the basic follicle stimulating hormone (FSH) level data is collected
  • a is selected from any value in the range of 0.0250603 to 1.1726555, and a is preferably 0.5988579;
  • b is selected from any value from -0.021215 to -0.000214, and b is preferably -0.010715;
  • c is selected from any value from -0.031133 to 0.0043087, and c is preferably -0.013412;
  • d is selected from any value in the range of 0.151584 to 0.2904983, and d is preferably 0.2210412;
  • f is selected from any value in the range of 0.2445264 to 0.3871042, and f is preferably 0.3158153.
  • g is selected from any value from -0.447201 to 0.9161863, preferably 0.2344927;
  • h is selected from any value in the range of -0.017165 to 0.0039328, preferably -0.006616;
  • i is selected from any value in the range of 0.1318094 to 0.3113979, preferably 0.2216036;
  • j is selected from any value in the range of 0.1901643 to 0.3850919, preferably 0.2876281;
  • k is selected from any value in the range of 0.0541966 to 0.2338079, preferably 0.1440023.
  • a standard GnRH antagonist ovarian stimulation protocol is performed as follows: human rFSH (e.g., Gonal-F alfa [Merck Serono, Germany], Puregon beta [MSD, USA], Urofollitropin [Livzon Pharmaceutical Group Inc., China] or Menotrophins [Livzon Pharmaceutical ]Group Inc., China]) began administration on the second day of the menstrual cycle.
  • human rFSH e.g., Gonal-F alfa [Merck Serono, Germany], Puregon beta [MSD, USA], Urofollitropin [Livzon Pharmaceutical Group Inc., China] or Menotrophins [Livzon Pharmaceutical ]Group Inc., China]
  • the starting dose of human rFSH was selected based on age, AMH level, basal FSH level, AFC level, and BMI.
  • the dose of rFSH was further adjusted according to the size and number of growing follicles observed by ultrasound and the monitoring of serum E2 levels during ova
  • hCG Chogonadotropin alfa, Merck Serono
  • Oocyte recovery was performed 36-38 hours after hCG administration. Transfer of one or two embryos or embryo cryopreservation. Luteal phase progesterone support (progesterone vaginal gel, Merck Serono) was then provided to the patient or subject.
  • Follicles with a diameter of 2–10 mm in both ovaries were measured by transvaginal ultrasound scan on day 2 of the menstrual cycle to calculate AFC.
  • Blood was drawn from the subjects on the second and sixth day of menstruation.
  • the tests on the second day included AMH, inhibin B concentration, age, body mass index (BMI), FSH, AFC, LH, E 2 , testosterone (T) and androstenedione (AND).
  • Serum AMH concentration and inhibin B concentration were measured using an ultrasensitive ELISA (Ansh Laboratories, Webster, TX, USA) kit, using the quality control provided with the kit.
  • AMH, inhibin B, FSH, and LH the coefficient of variation was determined to be less than 5% for tertiary or two-level controls, respectively.
  • E2 , T, and AND the three-level or two-level control of the assay coefficient of variation was less than 10%, respectively.
  • the measurement results are shown in Table 1.
  • Values are expressed as median; ⁇ level, dynamic level on day 6 minus day 2 for different ovarian reserve markers, NORs, number of oocytes retrieved; BMI, body mass index; T, testosterone; Ketone; NA, not applicable
  • Patent No.: ZL 201910780793.6 involves the use of basal anti-Müllerian hormone (AMH) levels, basal follicle-stimulating hormone (FSH) levels and antral follicle count (AFC) to predict the number of oocytes retrieved, that is, mainly The number of retrieved eggs is predicted by using basic level indicators, and the algorithm used plays an important role in the selection of the initial dose of ovulation induction drugs, but the adjustment of drug doses during ovulation induction should incorporate new indicators that are sensitive to ovulation induction drugs in order to improve Good predictor of retrieved oocytes.
  • AMH basal anti-Müllerian hormone
  • FSH basal follicle-stimulating hormone
  • AFC tral follicle count
  • basal level indicators preferentially reflect the size of the primordial follicle pool (i.e., ovarian reserve)
  • ovarian reserve there is heterogeneity in the ovarian response to exogenous FSH stimulation among individuals with the same ovarian reserve during ovarian stimulation. Therefore, some researchers proposed to use the dynamic changes of ovarian reserve markers during ovulation induction to predict ovarian responsiveness.
  • Tal R, Pu D, Liu L, Liu J, Wu J Comparisons of inhibin B versus antimullerian hormone in poor ovarian responders undergoing in vitro fertilization.
  • Inhibin B is mainly produced by FSH-sensitive follicles, and administration of exogenous FSH promotes ovarian growth and increases inhibin B levels [Broekmans FJ, Soules MR, Fauser BC: Ovarian Aging: Mechanisms and Clinical Consequences. Endocr Rev 2009, 30(5):465-493].
  • inhibin B and other hormone indicators commonly used in clinical practice, in order to establish an optimal model through a more scientific index screening method, rather than preconceived that inhibin B may be a better indicator , which precludes other metrics.
  • this application provides two models.
  • the initial variables included in the model were age, BMI, basal FSH, AMH on the second and sixth day, inhibin B, LH, E2, P, testosterone, and androstenedione, and finally selected subjects
  • the four indexes of age, basic anti-Müllerian hormone (AMH) level, basic follicle stimulating hormone (FSH) level and inhibin B level dynamic change ( ⁇ INHB) were used as indicators to predict the number of mature oocytes.
  • the initial variables included in the model were age, BMI, basal FSH, AFC on day two, AMH on days two and six, inhibin B, LH, E2, P, testosterone, and androstenedione,
  • the age of the subjects were finally selected as indicators for predicting the number of mature oocytes .
  • AFC basic anti-Müllerian hormone
  • AFC basic antral follicle count
  • ⁇ INHB dynamic change of inhibin B level
  • model 1 (without AFC) in the training set and validation set are 0.610 and 0.615
  • R2 of model 2 (with AFC) in the training set and validation set are 0.643 and 0.616, respectively.
  • the initial variables included in model 1 and model 2 are basically the same, except that model 2 uses the AFC index, while model 1 uses the FSH level, but the effects of both models are good.
  • model 1 uses the AFC index
  • model 1 uses the FSH level, but the effects of both models are good.
  • Those skilled in the art can arbitrarily select the first model (model 1) or the second model (model 2) for calculation or prediction according to the actual situation or the data obtained from the subject in the previous period.
  • AFC For the measurement of AFC, there are many interfering factors. Even in single-center studies, although both the definition of AFC and the ultrasound instrumentation are uniform, AFC is still heavily influenced by the heterogeneity of individual clinicians performing AFC measurements.
  • the first model of this application avoids the use of AFC as an indicator, and at the same time incorporates the dynamics of inhibin B as an indicator, and finally selects the subject's age, basal anti-Müllerian hormone (AMH) level, and basal follicle-stimulating hormone level.
  • AFC basal anti-Müllerian hormone
  • FSH dynamic change of inhibin B level
  • ⁇ INHB dynamic change of inhibin B level
  • the distribution of the number of retrieved oocytes was first determined for the data of the 669 patients described above. Since the number of retrieved oocytes is count data, Poisson distribution or negative binomial distribution can usually be considered. As shown in Figure 1, the number of retrieved oocytes is obviously more in line with the negative binomial distribution. In this embodiment, negative binomial regression is selected to build a statistical model. The selection of predictive indicators adopts pruned forward method and 30% holdback verification. Using the software JMP Pro v.14, a predictive model is established, and the data set composed of the above-mentioned 669 patients is randomized. It is divided into two parts, one as a training set (468 data, 70%) and the other as a validation set (201 data, 30%).
  • model the model in the training set and verify the model effect in the validation set The selection of the prediction model is mainly based on the negative log-likelihood value in the validation set. The lower the negative log-likelihood value in the validation set, the better the model is.
  • Table 3 The performance of the model in the training set and validation set
  • NROs represents the number of mature oocytes
  • age represents the age of the subject
  • FSH represents the basic follicle-stimulating hormone level of the subject before ovulation induction treatment
  • AMH represents the basic anti-Müllerian hormone level of the subject before ovulation induction treatment
  • ⁇ INHB represents the dynamic change of inhibin B level in the early stage of the subject's ovulation induction treatment.
  • AMH refers to the anti-Müllerian hormone concentration in the venous blood of the subject at any time point during the menstrual period before ovulation induction treatment.
  • FSH refers to the follicle-stimulating hormone concentration in the venous blood of female subjects on the second day of menstruation before ovulation induction treatment.
  • ⁇ venous blood refers to the difference between the concentration of serum inhibin B on the 6th day of menstruation and the concentration of inhibin B in the venous blood of female subjects on the 2nd day of menstruation when female subjects receive GnRH antagonist regimen for ovulation induction treatment .
  • a is selected from any value in the range of 0.0250603 to 1.1726555, and a is preferably 0.5988579;
  • b is selected from any value from -0.021215 to -0.000214, and b is preferably -0.010715;
  • c is selected from any value from -0.031133 to 0.0043087, and c is preferably -0.013412;
  • d is selected from any value in the range of 0.151584 to 0.2904983, and d is preferably 0.2210412;
  • f is selected from any value in the range of 0.2445264 to 0.3871042, and f is preferably 0.3158153.
  • the prediction effect of the model constructed for the training set and verification set using the above method is shown in Table 3, Figure 2 and Figure 3.
  • the abscissa shows the NROs predicted by the model, that is, the predicted number of oocytes obtained by the subject undergoing the standard antagonist protocol for ovulation induction, and the ordinate shows the actual detected number of oocytes of the subject
  • the obtained number of oocytes shows that the model constructed above has achieved good prediction results in both the training set and the verification set, and the predicted data is highly consistent with the actual detected number.
  • the model of the present invention reflects activated follicle growth after increasing ⁇ INHB, although the model of the present invention does not include AFC, the generalized R2 in the model increases significantly from 0.49 and 0.52 to 0.61 in the training set and validation set, respectively and 0.62. It can be seen that the model of the present invention is more accurate and has better performance. Compared with the model described in CN201910780793.6, the scatter point distribution is closer to the diagonal line, especially the predicted normal ovarian responders (predicted ⁇ 15 oocytes) cell).
  • the outcome variable is consistent with the first model, which is the number of oocytes retrieved, and the data is also the same, so the negative binomial regression is still used for analysis.
  • model the model in the training set and verify the model effect in the validation set The selection of the prediction model is mainly based on the negative log-likelihood value in the validation set. The lower the negative log-likelihood value in the validation set, the better the model is.
  • NROs represents the number of mature oocytes
  • age represents the age of the subject
  • AFC represents the number of all visible follicles with a diameter of 2-10mm in the two ovaries of the subject on the second day of menstruation
  • AMH represents the subject's ovulation induction Baseline anti-Müllerian hormone level before treatment
  • ⁇ INHB represents the dynamic change of inhibin B level in the early stage of the subject's ovulation induction treatment.
  • AMH refers to the concentration of anti-Müllerian hormone in the venous blood of the subject at any point in the menstrual period before ovulation induction treatment.
  • AFC refers to the number of all visible follicles with a diameter of 2-10mm in the two ovaries of female subjects on the second day of menstruation before ovulation induction treatment.
  • ⁇ INHB refers to the difference between the serum inhibin B concentration on day 6 of menstruation and the concentration of inhibin B in venous blood of female subjects on day 2 of menstruation when female subjects receive GnRH antagonist regimen for ovulation induction treatment.
  • g is selected from any value in the range of -0.447201 to 0.9161863, preferably 0.2344927;
  • h is selected from any value in the range of -0.017165 to 0.0039328, preferably -0.006616;
  • i is selected from any value in the range of 0.1318094 to 0.3113979, preferably 0.2216036;
  • j is selected from any value in the range of 0.1901643 to 0.3850919, preferably 0.2876281;
  • k is selected from any value in the range of 0.0541966 to 0.2338079, preferably 0.1440023.
  • Table 5 The performance of the model in the training set and validation set
  • the prediction effect of the model constructed for the training set and the verification set using the above method is shown in Table 5, Figure 4 and Figure 5.
  • the abscissa shows the NROs predicted by the model, that is, the predicted number of oocytes obtained by the subject undergoing ovulation induction with a standard antagonist protocol, and the ordinate shows the actual detected number of oocytes obtained by the subject.
  • the number of oocytes it can be seen that the model constructed above has achieved good prediction results in both the training set and the verification set, and the predicted data is in good agreement with the actual detected number.

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Abstract

一种用于预测受试者的成熟卵母细胞数量的系统，包括：数据采集模块，其用于获取受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、早卵泡期抑制素B水平动态变化(ΔINHB/促排卵周期月经第六天与第二天抑制素B的差值)的数据；以及成熟卵母细胞数量计算模块，其用于对数据采集模块中的获取的上述数据进行计算，从而计算出受试者的获取的成熟卵母细胞数量(NROs)。本发明的系统和方法利用早卵泡期抑制素B水平动态变化作为评价指标，代替了现有技术中具有诸多缺陷的AFC指标，取得了更优的获卵数预测效果。本系统可用于促排卵过程中(如促排卵周期月经第六天)根据动态变化指标预测获卵数，从而进行促排卵药物剂量的调整。

Description

预测受试者卵巢刺激过程中获得的卵母细胞数量的系统和方法 技术领域
本发明涉及一种用于预测接受标准促排卵治疗(非微刺激)的受试者在卵巢刺激过程中获得的卵母细胞数量的系统和方法。
背景技术
对于经受控制性卵巢刺激(Controlled ovarian stimulation，COS)和IVF/ICSI周期的女性，获取的卵母细胞数量(The number of retrieved oocytes,NROs)被认为是成功怀孕的强有力的替代预后标志物。最佳NROs有助于提高活产率(Live-birth-rate，LBR)。
本研究团队之前研发了一种利用基础卵巢储备指标(促排卵治疗前的指标)来预测促排卵治疗获卵数的系统和方法，该系统对促排卵治疗起始剂量的选择非常重要，但是相同的基础卵巢储备状态对促排药物(重组FSH)的反应性也存在较大差异，既往临床大夫常常根据个人经验，用治疗过程中超声下的卵泡大小和数量结合LH(黄体生成素)、雌二醇(E2)、孕酮(P)的生长变化来估算预期获卵数，并进行促排卵药物剂量的调整，但是截至目前，国际范围内对于促排卵过程中促排卵药物(重组人源FSH)剂量的调整主要依靠主观经验，没有统一的标准。
发明内容
由于预测NROs的必要性，本申请发明人的研究试图结合基础指标和活化指标，根据促排卵过程中指标的变化，建立促排卵过程中预测GnRH拮抗剂方案中获卵数的可靠数学模型，以便促排卵过程促排卵药物剂量的调整。本申请发明人开发的技术方案对获卵数和接受辅助生殖技术治疗的妇女的妊娠结果有益。
本发明的目的在于提供一种有效的系统，其可以用于预测如果一个受试 者接受标准促排卵治疗，其获得的成熟卵母细胞的数量，未来可以结合其他系统来更好的指导促排卵方案和重组FSH剂量的选择。本发明探索可靠的系统来预测接受标准促排卵治疗(即采用足量rFSH进行促排卵治疗，而非微刺激)方案中的NROs。由于GnRH拮抗剂方案中的激素水平实际上是任何人的基本激素水平，因此本发明的系统在一般人群中对于COS前评估和卵巢刺激期间的临床咨询可能具有重要意义。利用本发明的系统或方法对NROs和接受辅助生殖技术(ART)治疗的女性的妊娠结果有益。
在卵巢刺激期间预测获取的成熟卵母细胞(Number of retrieved oocytes，NROs)的数量是进行有效和安全治疗的唯一方法。逻辑回归分析已广泛用于预测卵巢反应的不良与否。但是，将结局变量NROs分为两类(即低反应与否)对个体来说不够具体和充分。目前，针对预测特定NROs的研究还非常少，这妨碍了辅助生殖技术中个体化治疗的发展。
综上，本发明涉及如下内容：
1.一种用于预测受试者的成熟卵母细胞数量的系统，其包括：
数据采集模块，其用于获取受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB/促排卵周期月经第六天和第二天抑制素B的差值)的数据；以及
成熟卵母细胞数量计算模块，其用于对数据采集模块中的获取的上述数据进行计算，从而计算出受试者在促排卵周期获得的成熟卵母细胞数量(NROs)。
2.根据权利要求1所述的系统，其中，
所述受试者是将要接受标准(足量刺激而非微刺激)促排卵治疗的受试者，所述受试者的成熟卵母细胞数量是在受试者接受促排卵治疗后卵巢刺激过程中获得的直径在18毫米以上的成熟卵母细胞数量。
3.根据权利要求1或2所述的系统，其中，
在成熟卵母细胞数量计算模块中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于计算受试者成熟卵母细胞数量(NROs)的公式。
4.根据权利要求1～3中任一项所述的系统，其中，
在数据采集模块中，收集的基础抗缪勒氏管激素(AMH)水平是指受试者在促排卵治疗前月经期任意时间点静脉血中的抗缪勒氏管激素浓度。
5.根据权利要求1～4中任一项所述的系统，其中，
在数据采集模块中，收集的基础卵泡刺激素(FSH)水平是指女性受试者促排卵治疗前月经第2天的静脉血中的卵泡刺激素浓度。
6.根据权利要求1～5中任一项所述的系统，其中，
在数据采集模块中，收集的基础窦卵泡计数(AFC)是指阴道B超计数女性受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数。
7.根据权利要求1～6中任一项所述的系统，其中，
在数据采集模块中，收集的抑制素B水平动态变化(ΔINHB)是指促排卵治疗早期的抑制素B水平动态变化(ΔINHB)，优选为女性受试者接受GnRH拮抗剂方案促排卵治疗周期月经第6天的血清抑制素B浓度与月经第2天的静脉血中的抑制素B浓度的差值。
8.根据权利要求3～6中任一项所述的系统，其中，
在成熟卵母细胞数量计算模块中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于预测受试者成熟卵母细胞数量(NROs)的公式是将现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据利用负二项分布拟合得到的计算公式；
该公式能够利用所述数据采集模块采集的受试者的年龄数据、受试者的基础抗缪勒氏管激素(AMH)水平数据、受试者的基础卵泡刺激素(FSH)水平数据或基础窦卵泡计数(AFC)数据和受试者的抑制素B水平动态变化(ΔINHB)数据来计算该受试者获得的成熟卵母细胞数量(NROs)。
9.根据权利要求8所述的系统，其中，
当数据采集模块收集的是基础卵泡刺激素(FSH)水平时(未进行双侧卵巢窦卵泡数/AFC的超声检查)，所述公式为如下公式一：
ln(NROs)＝a+b*年龄+c*基础FSH+d*ln[基础AMH]+f*ln[ΔINHB](公式 一)；
其中，a选自0.0250603～1.1726555中的任意数值，优选为0.5988579；
b选自-0.021215～-0.000214中的任意数值，优选为-0.010715；
c选自-0.031133～0.0043087中的任意数值，优选为-0.013412；
d选自0.151584～0.2904983中的任意数值，优选为0.2210412；
f选自0.2445264～0.3871042中的任意数值，优选为0.3158153。
10.根据权利要求8所述的系统，其中，
当数据采集模块收集的是基础窦卵泡计数(AFC)时，所述公式为如下公式二：
ln(NROs)＝g+h*年龄+i*ln[基础AMH]+j*ln[ΔINHB]+k*ln[AFC](公式二)；
其中，g选自-0.447201～0.9161863中的任意数值，优选为0.2344927；
h选自-0.017165～0.0039328中的任意数值，优选为-0.006616；
i选自0.1318094～0.3113979中的任意数值，优选为0.2216036；
j选自0.1901643～0.3850919中的任意数值，优选为0.2876281；
k选自0.0541966～0.2338079中的任意数值，优选为0.1440023。
11.一种用于预测受试者的成熟卵母细胞数量的方法，其包括：
数据采集步骤，其获取受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据；以及
成熟卵母细胞数量计算步骤，其对数据采集步骤中的获取的上述数据进行计算，从而计算出受试者的获取的成熟卵母细胞数量(NROs)。
12.根据项11所述的方法，其中，
所述受试者是将要接受标准促排卵治疗的受试者，所述受试者的成熟卵母细胞数量是在受试者接受促排卵治疗后卵巢刺激过程中获得的卵泡直径大于18毫米的成熟卵母细胞数量。
13.根据项11或12所述的方法，其中，
在成熟卵母细胞数量计算步骤中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于计算受试者成熟卵母细胞数量 (NROs)的公式。
14.根据项11～13中任一项所述的方法，其中，
在数据采集步骤中，收集的基础抗缪勒氏管激素(AMH)水平是指受试者在促排卵治疗前月经期任意时间点静脉血中的抗缪勒氏管激素浓度。
15.根据项11～14中任一项所述的方法，其中，
在数据采集步骤中，收集的基础卵泡刺激素(FSH)水平是指女性受试者促排卵治疗前月经第2天的静脉血中的卵泡刺激素浓度。
16.根据项11～15中任一项所述的方法，其中，
在数据采集步骤中，收集的基础窦卵泡计数(AFC)是指阴道B超计数女性受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数。
17.根据项11～16中任一项所述的方法，其中，
在数据采集步骤中，收集的抑制素B水平动态变化(ΔINHB)是指促排卵治疗早期的抑制素B水平动态变化(ΔINHB)，优选为女性受试者接受GnRH拮抗剂方案促排卵治疗促排卵周期月经第6天的血清抑制素B浓度与女性受试者促排卵周期月经第2天的静脉血中的抑制素B浓度的差值。
18.根据项13～16中任一项所述的方法，其中，
在成熟卵母细胞数量计算步骤中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于预测受试者成熟卵母细胞数量(NROs)的公式是将现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据利用负二项分布拟合得到的计算公式；
该公式能够利用所述数据采集步骤采集的受试者的年龄数据、受试者的基础抗缪勒氏管激素(AMH)水平数据、受试者的基础卵泡刺激素(FSH)水平数据或基础窦卵泡计数(AFC)数据和受试者的抑制素B水平动态变化(ΔINHB)数据来计算该受试者获得的成熟卵母细胞数量(NROs)。
19.根据项18所述的方法，其中，
当数据采集步骤收集的是基础卵泡刺激素(FSH)水平时，所述公式为如下公式一：
ln(NROs)＝a+b*年龄+c*基础FSH+d*ln[基础AMH]+f*ln[ΔINHB](公式一)；
其中，a选自0.0250603～1.1726555中的任意数值，优选为0.5988579；
b选自-0.021215～-0.000214中的任意数值，优选为-0.010715；
c选自-0.031133～0.0043087中的任意数值，优选为-0.013412；
d选自0.151584～0.2904983中的任意数值，优选为0.2210412；
f选自0.2445264～0.3871042中的任意数值，优选为0.3158153。
20.根据项18所述的方法，其中，
当数据采集步骤收集的是基础窦卵泡计数(AFC)时，所述公式为如下公式二：
ln(NROs)＝g+h*年龄+i*ln[基础AMH]+j*ln[ΔINHB]+k*ln[AFC](公式二)；
其中，g选自-0.447201～0.9161863中的任意数值，优选为0.2344927；
h选自-0.017165～0.0039328中的任意数值，优选为-0.006616；
i选自0.1318094～0.3113979中的任意数值，优选为0.2216036；
j选自0.1901643～0.3850919中的任意数值，优选为0.2876281；
k选自0.0541966～0.2338079中的任意数值，优选为0.1440023。
发明的效果
一般来说如果能够准确地预测受试者获卵数时，当预测的获卵数越多，促排卵治疗过程中需要的促性腺激素使用量越低，反之，则促排卵过程中需要的促性腺激素使用量越多。利用本发明的系统和方法可以更为准确地预测如果受试者接受标准GnRH拮抗剂方案促排卵治疗，其卵巢刺激过程中获得的成熟卵母细胞数量。并且，本发明的系统和方法利用抑制素B水平动态变化作为评价指标，代替了现有技术中具有诸多缺陷的AFC指标，而且取得了更优的预测效果。总之，促排卵过程中药物剂量的调整主要基于对获卵数的预测，本申请涉及的方法或系统可用于促排卵过程中(如促排卵周期月经第六天)根据用药后指标的变化预测获卵数，从而进行促排卵药物剂量的调整。
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是第一种模型和第二种模型拟合结局变量的分布图；
图2是第一种模型在训练集中的预测效果；
图3是第一种模型在验证集中的预测效果；
图4是第二种模型在训练集中的预测效果；
图5是第二种模型在验证集中的预测效果。
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。
变量类型：在统计学中，变量类型可分为定量变量与定性变量(也称分类变量)两种。
定量变量是用于描述事物数量和个数的变量，又可分为连续型和离散型。连续型变量是指在一定区间内可以任意取值的变量，其数值是连续不断的，可以有小数点。例如，血压值、血糖值，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。离散型变量是指其取值只能是自然数或整数单位的变量。例如，疼痛分值，病灶转移个数，获卵数等，只能是正数，不能取小数点，这种变量的数值一般用计数方法取得。
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。
泊松分布(Poisson distribution)是一种统计与概率学里常见到的离散概率分布(discrete probability distribution)。泊松分布适合于描述单位时间(或空间)内随机事件发生的次数。如某一固定空间和时间内出现的疾病例数，某疾病复发的次数，某病灶转移的部位数，某患者呕吐次数，等等。
负二项分布是统计学上一种离散概率分布。满足以下条件的称为负二项分布：实验包含一系列独立的实验，每个实验都有成功、失败两种结果，成功的概率是恒定的，实验持续到r次成功，r为正整数。负二项分布与Poisson分布类似，也可用于描述某单位时间、空间内某罕见事件的相对频率。其与Poisson分布不同之处在于，Poisson分布只能用于描述独立性事件，而负二项分布常用于描述聚集性事件，如钉螺在土壤中的分布、某传染病的分布等。通常如果计数资料发现其均值大于方差的现象，此时Poisson分布往往拟合效果不好，可考虑负二项分布。
在本文中，抗缪勒氏管激素(AMH)是指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。
在本文中，卵泡刺激素(FSH)是指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。
近来，血清抑制素B水平被认为是卵泡发育的标志物。抑制素B通过内分泌和旁分泌作用参与正常月经周期中卵泡的选择，促进卵泡的生长。抑制素B的作用之一是在自然月经周期的卵泡中期下调FSH的分泌。它还发挥旁分泌作用，刺激卵囊膜细胞产生雄激素和LH。抑制素B的分泌在卵泡早期达到峰值，卵泡直径为10-12毫米。已经证明，与基础标记相比，第5天(早期卵泡期)抑制素B是卵巢反应差和活产的优良标记。抑制素B主要由FSH敏感的卵泡产生，外源性FSH的施用导致其在生长的卵泡中增加。与此一致，本申请发明人发现抑制素B水平动态变化(ΔINHB)即促排卵周期月经第6天抑制素B浓度与第2天抑制素B浓度的差值是预测取卵数量的最佳标志物。
BMI是国际上常用的衡量人体肥胖程度和是否健康的重要标准，主要用于统计分析。肥胖程度的判断不能采用体重的绝对值，它天然与身高有关。因此，BMI通过人体体重和身高两个数值获得相对客观的参数，并用这个参数所处范围衡量身体质量。BMI＝体重/身高的平方(国际单位kg/m 2)。
在本文中，窦卵泡计数(AFC)是指月经2-4天两个卵巢中直径为2-10mm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。
促黄体生成素(LH)由腺垂体细胞分泌的一种糖蛋白类促性腺激素，可促进胆固醇在性腺细胞内转化为性激素。对于女性来说，与促卵泡激素(FSH)共同作用促进卵泡成熟，分泌雌激素、排卵，以及黄体的生成和维持，分泌孕激素和雌激素。对于男性来说，促黄体生产素促成睾丸间质细胞合成和释放睾酮。LH水平是指女性受试者月经2-4天的静脉血血清样本中的LH浓度。
基础E 2水平是指雌二醇水平，雌二醇是一种甾体雌激素。有α，β两种类型，α型生理作用强。它有很强的性激素作用，所以认为它或它的酯实际上是卵巢分泌的最重要的性激素。在本申请中检测基础雌二醇水平是女性受试者月经2-4天的静脉血血清样本中的雌二醇浓度。
本申请发明人团队之前研发了一种利用基础卵巢储备指标(促排卵治疗前的指标)来预测促排卵治疗获卵数的系统和方法，该系统对促排卵治疗起始剂量的选择非常重要，但是相同的基础卵巢储备状态对促排药物(重组FSH)的反应性也存在较大差异，既往临床大夫常常应用治疗过程中超声检 测的卵泡数结合LH(黄体生成素)、雌二醇(E2)、孕酮(P)的生长变化来猜测预期获卵数，并进行计量的调整，但是截至目前，国际范围内对于重组FSH剂量的调整主要依靠主观经验，没有统一的标准。
为了解决上述问题，本发明涉及一种利用基础卵巢储备指标结合卵巢刺激早期活化的卵巢储备指标建立模型，预测受试者在接受标准GnRH拮抗剂方案促排卵治疗时，其卵巢刺激过程中获得的卵母细胞数量的系统，其包括：数据采集模块，其用于获取受试者的基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平、抑制素B早期水平动态变化(ΔINHB)的数据(即促排卵周期月经第六天血清抑制素B水平与第二天之差)；以及成熟卵母细胞数量计算模块，其用于将数据采集模块中的获取的上述信息进行计算，从而计算出受试者接收GnRH拮抗剂方案促排卵治疗后获得的成熟卵母细胞数量(NROs)，以期将基础水平卵巢储备指标与活化的卵巢储备指标结合，以更好的预测获卵数，并有助于在卵巢刺激治疗早期，根据第六天抑制素B指标的变化，调整重组FSH(一种促排卵药)剂量，减少医源性卵巢低反应或高反应、预防卵巢过度刺激、并降低卵巢刺激期间的成本。
本申请所述受试者是将要接受标准GnRH拮抗剂方案促排卵治疗的受试者，所述受试者的成熟卵母细胞数量是在受试者接受促排卵治疗后卵巢刺激过程中获得的卵泡直径大于18毫米的成熟卵母细胞数量。
其中，本申请所述的标准GnRH拮抗剂卵巢刺激方案如下进行：人重组FSH(人rFSH)(例如，Gonal-F alfa[Merck Serono，Germany]，Puregon beta[MSD，USA],Urofollitropin[Livzon Pharmaceutical Group Inc.，China]或Menotrophins[Livzon Pharmaceutical]Group Inc.，China])在月经周期第2天开始给药。基于年龄、基础AMH水平、基础FSH水平、基础AFC水平以及BMI等对人rFSH的起始剂量来进行选择。根据超声观察到的生长卵泡的大小和数量以及监测卵巢刺激期间的血清E 2水平进一步进行rFSH剂量的调整。当生长的卵泡直径达到10-12mm时，开始GnRH拮抗剂治疗。当通过超声观察到至少两个优势卵泡直径超过18mm时，注射hCG(Choriogonadotropin alfa，Merck Serono)剂量为5000-10000IU以触发最终的卵母细胞成熟。在hCG施用后36-38小时进行卵母细胞回收。移植一至两个胚胎或进行胚胎冷冻保存。之后向受试者提供黄体期孕酮支持(孕酮阴道凝胶，Merck Serono)。
在本申请的具体的实施方案中，本申请涉及的系统和方法是针对受试者是接受如上所述标准GnRH拮抗剂方案促排卵治疗的受试者。
本申请涉及一种用于预测受试者卵巢刺激过程中获得的卵母细胞数量的系统，其包括：数据采集模块，其用于获取受试者的基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平、抑制素B水平动态变化(ΔINHB)的数据；以及预测卵巢刺激过程中获得的成熟卵母细胞数量的模块，其用于对数据采集模块中的获取的上述数据进行计算，从而计算出受试者的获取的成熟卵母细胞数量(NROs)。
本领域技术人员知道通常影响受试者获取的卵母细胞数量的因素有很多，例如BMI指数、不孕症持续时间、先前体外受精/卵胞浆内单精子注射-胚胎移植(IVF/ICSI-ET)尝试次数、血清基础E 2水平、FSH水平和LH水平、血清AMH水平、左右卵巢AFCs、不孕症的第一、第二、第三、第四和第五原因、传统或轻度卵巢刺激周期、卵巢刺激类型/COS方案、重组rFSH的起始剂量和总剂量、rFSH治疗的持续时间(天)、rFSH的名称、人绒毛膜促性腺激素(hCG)触发日的子宫内膜厚度等等，在本申请中，本申请的发明人经过对各指标的筛选，最终确认了受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或双侧窦卵泡数(AFC)、抑制素B水平动态变化(ΔINHB)这四个重要的参数，来计算受试者的NROs。
在本文中，对于数据采集模块没有任何限定，只要可以用于获取受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平、抑制素B水平动态变化(ΔINHB)的数据。其中，具体来说，数据采集模块获取的基础抗缪勒氏管激素(AMH)水平是指女性受试者在月经期任意时间点静脉血中的抗缪勒氏管激素浓度，数据采集模块获取的所述基础卵泡刺激素(FSH)水平是指女性受试者月经第2天的静脉血中的卵泡刺激素浓度，数据采集模块获取的基础窦卵泡计数(AFC)是指阴道B超计数女性受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数，数据采集模块获取的所述抑制素B水平动态变化(ΔINHB)是指女性受试者促排卵周期月经第6天的静脉血中的抑制素B浓度与女性受试者月经第2天的静脉血中的抑制素B浓度的差值。基于需要预测卵巢刺激过程中获得的卵母细胞数量的受试者，可以采取其上述给定期限内的数据，从而基于本申请的方法和系统来 进行获卵数的预测。
在本文中，利用成熟卵母细胞数量计算模块对数据采集模块中的获取的上述数据进行计算，从而计算出受试者的获取的成熟卵母细胞数量(NROs)。首先，应当理解，在该模块中预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据，以及基于所述预存的患者的数据和负二项分布拟合而成的用于预测受试者在接受标准GnRH拮抗剂方案促排卵治疗时，在卵巢刺激过程中获得的成熟卵母细胞数量(NROs)的公式。利用这样预存好的公式，可以针对任意受试者进行计算。
具体来说，这个预存的公式是利用预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的。
在计算时，这个预存的公式是利用所述数据采集模块采集的受试者的年龄数据、受试者的基础AMH水平数据、受试者的基础FSH水平数据或基础窦卵泡计数(AFC)，以及受试者的抑制素B水平动态变化(ΔINHB)数据来计算受试者获得的成熟卵母细胞数量(NROs)的公式。
进一步，本申请的发明人构建了用于预测NROs的具体的公式，当数据采集模块采集的是基础卵泡刺激素(FSH)水平数据时，具体的公式为如下公式一：
ln(NROs)＝a+b*年龄+c*FSH+d*ln[AMH]+f*ln[ΔINHB](公式一)；
进一步地，在所述公式一中，
a选自0.0250603～1.1726555中的任意数值，a优选为0.5988579；
b选自-0.021215～-0.000214中的任意数值，b优选为-0.010715；
c选自-0.031133～0.0043087中的任意数值，c优选为-0.013412；
d选自0.151584～0.2904983中的任意数值，d优选为0.2210412；
f选自0.2445264～0.3871042中的任意数值，f优选为0.3158153。
当数据采集模块采集的是基础窦卵泡计数(AFC)时，具体的公式为如下公式二：
ln(NROs)＝g+h*年龄+i*ln[基础AMH]+j*ln[ΔINHB]+k*ln[AFC](公式 二)
进一步地，在所述公式二中，
g选自-0.447201～0.9161863中的任意数值，优选为0.2344927；
h选自-0.017165～0.0039328中的任意数值，优选为-0.006616；
i选自0.1318094～0.3113979中的任意数值，优选为0.2216036；
j选自0.1901643～0.3850919中的任意数值，优选为0.2876281；
k选自0.0541966～0.2338079中的任意数值，优选为0.1440023。
本发明还涉及一种用于预测受试者的成熟卵母细胞数量的方法，其包括：
数据采集步骤，用于获取受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据；以及
成熟卵母细胞数量计算步骤，用于对数据采集步骤中的获取的上述数据进行计算，从而计算出受试者的获取的成熟卵母细胞数量(NROs)。
在上述方法中，所述受试者是将要接受标准GnRH拮抗剂方案促排卵治疗的受试者，所述受试者的成熟卵母细胞数量是在受试者接受促排卵治疗后卵巢刺激过程中获得的卵泡直接大于18毫米的成熟卵母细胞数量。
在上述方法中，在成熟卵母细胞数量计算步骤中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于计算受试者成熟卵母细胞数量(NROs)的公式。
在上述方法中，在数据采集步骤中，收集的基础抗缪勒氏管激素(AMH)水平是指受试者在促排卵治疗前月经期任意时间点静脉血中的抗缪勒氏管激素浓度。
在上述方法中，在数据采集步骤中，收集的基础卵泡刺激素(FSH)水平是指女性受试者促排卵治疗前月经第2天的静脉血中的卵泡刺激素浓度。
在上述方法中，在数据采集步骤中，收集的基础窦卵泡计数(AFC)是指阴道B超计数女性受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数。
在上述方法中，在数据采集步骤中，收集的基础窦卵泡计数(AFC)是指 阴道B超计数女性受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数。
在上述方法中，在数据采集步骤中，收集的抑制素B水平动态变化(ΔINHB)是指女性受试者接受GnRH拮抗剂方案促排卵治疗促排卵周期月经第6天的血清抑制素B浓度与女性受试者促排卵周期月经第2天的静脉血中的抑制素B浓度的差值。
在上述方法中，在成熟卵母细胞数量计算步骤中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于预测受试者成熟卵母细胞数量(NROs)的公式是将现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据利用负二项分布拟合得到的计算公式。
该公式能够利用所述数据采集模块采集的受试者的年龄数据、受试者的基础抗缪勒氏管激素(AMH)水平数据、受试者的基础卵泡刺激素(FSH)水平数据或基础窦卵泡计数(AFC)，以及受试者的抑制素B水平动态变化(ΔINHB)数据来计算该受试者获得的成熟卵母细胞数量(NROs)。
当数据采集步骤中，收集的是基础卵泡刺激素(FSH)水平数据时，
在上述方法中，所述公式为如下公式一：
ln(NROs)＝a+b*年龄+c*FSH+d*ln[AMH]+f*ln[ΔINHB](公式一)；
在上述方法中，在所述公式一中，
a选自0.0250603～1.1726555中的任意数值，a优选为0.5988579；
b选自-0.021215～-0.000214中的任意数值，b优选为-0.010715；
c选自-0.031133～0.0043087中的任意数值，c优选为-0.013412；
d选自0.151584～0.2904983中的任意数值，d优选为0.2210412；
f选自0.2445264～0.3871042中的任意数值，f优选为0.3158153。
当数据采集步骤中，收集的是基础窦卵泡计数(AFC)时，
在上述方法中，所述公式为如下公式二：
ln(NROs)＝g+h*年龄+i*ln[基础AMH]+j*ln[ΔINHB]+k*ln[AFC](公式二)；
其中，g选自-0.447201～0.9161863中的任意数值，优选为0.2344927；
h选自-0.017165～0.0039328中的任意数值，优选为-0.006616；
i选自0.1318094～0.3113979中的任意数值，优选为0.2216036；
j选自0.1901643～0.3850919中的任意数值，优选为0.2876281；
k选自0.0541966～0.2338079中的任意数值，优选为0.1440023。
实施例
用于构建模型的受试者
基于2020年4月至2020年9月之间在北京大学第三医院接受治疗的669个患者获取的数据，初步进行模型构建。针对用于初步进行模型构建的患者，收集该患者的基本和临床特征，包括姓氏、病历号、序列号、年龄、BMI指数、不孕症持续时间、先前体外受精/卵胞浆内单精子注射-胚胎移植(IVF/ICSI-ET)尝试次数、血清基础E 2水平、FSH水平和LH水平、血清AMH水平、左右卵巢AFCs、不孕症的第一、第二、第三、第四和第五原因、传统或轻度卵巢刺激周期、卵巢刺激类型/COS方案、重组rFSH的起始剂量和总剂量、rFSH治疗的持续时间(天)、rFSH的名称、人绒毛膜促性腺激素(hCG)触发日的子宫内膜厚度、卵母细胞取出的日期和NROs。COS治疗
标准的GnRH拮抗剂卵巢刺激方案如下进行：人rFSH(例如，Gonal-F alfa[Merck Serono，Germany]，Puregon beta[MSD，USA]，Urofollitropin[Livzon Pharmaceutical Group Inc.，China]或Menotrophins[Livzon Pharmaceutical]Group Inc.，China])在月经周期第2天开始给药。基于年龄、AMH水平、基础FSH水平、AFC水平以及BMI等对人rFSH的起始剂量来进行选择。根据超声观察到的生长卵泡的大小和数量以及监测卵巢刺激期间的血清E 2水平进一步进行rFSH剂量的调整。当生长的卵泡直径达到10-12mm时，开始GnRH拮抗剂治疗。
当通过超声观察到至少两个优势卵泡直径超过18mm时，注射hCG(Choriogonadotropin alfa，Merck Serono)剂量为5000-10000IU以触发最终的卵母细胞成熟。在hCG施用后36-38小时进行卵母细胞回收。移植一至两个胚胎或进行胚胎冷冻保存。之后向患者或受试者提供黄体期孕酮支持(孕酮阴道凝胶，Merck Serono)。
用于模型构建的指标的测定
通过经阴道超声扫描在月经周期第2天测量两个卵巢中直径为2-10mm的卵泡，以计算AFC。在月经第二天和第六天对受试者进行抽血。其中，第二天的测试包括AMH、抑制素B浓度、年龄、体重指数(BMI),FSH、AFC、LH、E 2、睾酮(T)和雄烯二酮(AND)。第六天的测试包括抑制素B浓度、AMH、LH、E 2、睾酮(T)和雄烯二酮(AND)。其中，血清FSH、LH、E 2、T和AND测量测量均使用Siemens Immulite 2000免疫测定系统(SiemensHealthcare Diagnostics，Shanghai，PR China)进行。这些测定的质量控制由Bio-RAD实验室提供(Lyphochek Immunoassay Plus Control，Trilevel，目录号370，批号40340)。
使用超灵敏ELISA(Ansh Laboratories,Webster,TX,USA)试剂盒测量血清AMH浓度和抑制素B浓度，使用试剂盒提供的质量控制。对于AMH、抑制素B、FSH和LH，测定变异系数的三级或两级控制分别小于5％。对于E 2、T和AND，测定变异系数的三级或两级控制分别小于10％。测定结果如表1所示。
表1
Figure PCTCN2022078998-appb-000001
注：数值表示为中位数；Δ水平，不同卵巢储备标记物的第6天减去第2天的动态水平，NORs，获卵数；BMI，体重指数；T，睾酮；AND，雄烯二酮；NA，不适用
系统模型的构建
本申请发明人以往专利(专利号：ZL 201910780793.6)涉及使用基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平和窦卵泡计数(AFC)预测 获卵数，即主要是应用基础水平指标预测获卵数，其中使用的算法对促排卵药起始剂量的选择有重要作用，但是促排期间药物剂量的调整应该纳入新的对促排药物敏感的新的指标，以期更好的预测获卵数。
尽管基础水平指标优先反映原始卵泡池(即卵巢储备)的大小，但在卵巢刺激过程中具有相同卵巢储备的人存在卵巢对外源性FSH刺激反应的异质性。因此，有研究者提出利用促排卵过程中卵巢储备标志物的动态变化来预测卵巢反应性。[Tan R,Pu D,Liu L,Liu J,Wu J:Comparisons of inhibin B versus antimullerian hormone in poor ovarian responders undergoing in vitro fertilization.Fertil Steril 2011,96(4):905-911；Muttukrishna S,Suharjono H,McGarrigle H,Sathanandan M:Inhibin B and anti-Mullerian hormone:markers of ovarian response in IVF/ICSI patients，BJOG 2004,111(11):1248-1253.]最近有报道称抑制素B通过内分泌和旁分泌作用参与正常月经周期的卵泡选择，并促进FSH依赖性卵泡生长[Andersen CY,Schmidt KT,Kristensen SG,Rosendahl M,Byskov AG,Ernst E:Concentrations of AMH and inhibin-B in relation to follicular diameter in normal human small antral follicles.Hum Reprod 2010,25(5):1282-1287；Broekmans FJ,Soules MR,Fauser BC:Ovarian Aging:Mechanisms and Clinical Consequences.Endocr Rev 2009,30(5):465-493.]。抑制素B的分泌在卵泡早期达到峰值，此时卵泡直径为10-12毫米[Yding Andersen C:Inhibin-B secretion and FSH isoform distribution may play an integral part of follicular selection in the natural menstrual cycle.Mol Hum Reprod 2017,23(1):16-24]。已经证明，与基础标志物相比，促排卵过程中早卵泡期抑制素B是卵巢低反应和活产的优良标记[Penarrubia J,Peralta S,Fabregues F,Carmona F,Casamitjana R,Balasch J:Day-5 inhibin B serum concentrations and antral follicle count as predictors of ovarian response and live birth in assisted reproduction cycles stimulated with gonadotropin after pituitary suppression.Fertil Steril 2010,94(7):2590-2595]。抑制素B主要由FSH敏感的卵泡产生，外源性FSH的给药促进卵巢生长和抑制素B水平的增加[Broekmans FJ,Soules MR,Fauser BC:Ovarian Aging:Mechanisms and Clinical Consequences.Endocr Rev 2009,30(5):465-493]。
本申请发明人的研究前瞻性纳入了抑制素B以及临床常用的其他激素指标，以期通过更科学的指标筛选的方法建立最优的模型，而不是先入为主 的认为抑制素B可能是更有的指标，便预先排除了其他指标。
因此，本申请提供了两种模型。在第一种模型中，模型纳入的初始变量为年龄、BMI、基础FSH、第二天和第六天AMH、抑制素B、LH、E2、P、睾酮和雄烯二酮，最终选择受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平、抑制素B水平动态变化(ΔINHB)这四个指标作为预测成熟卵母细胞数量的指标。在第二种模型中，模型纳入的初始变量为年龄、BMI、基础FSH、第二天AFC、第二天和第六天AMH、抑制素B、LH、E2、P、睾酮和雄烯二酮，最终选择受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)这四个指标作为预测成熟卵母细胞数量的指标。可见在纳入AFC时FSH未被模型纳入分析，当无AFC指标是模型纳入FSH其他指标不变。模型1和模型2预测效果相似，模型1(无AFC)在训练集和验证集中的R2分别是0.610和0.615，模型2(有AFC)在训练集和验证集中的R2分别是0.643和0.616。模型1和模型2在最初建模时纳入的初始变量基本一致，只是模型2采用了AFC指标，而模型1采用了FSH水平，但是两个模型的效果均良好。本领域技术人员可以根据实际的情况或前期针对受试者所获得的数据来任意的选择第一种模型(模型1)或者第二种模型(模型2)来进行计算或预测。
对于AFC的测量，存在许多干扰因素。即使在单中心研究中，虽然AFC的定义和超声仪器都是统一的，但AFC仍然受到执行AFC测量的个体临床医生异质性的严重影响。
因此，本申请的第一种模型避免了使用AFC这个指标，同时纳入抑制素B的动态这个指标，最终选择受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平、抑制素B水平动态变化(ΔINHB)这四个指标作为预测成熟卵母细胞数量的指标。
在第一种模型(无AFC模型)中，针对上述669个患者的数据，首先确定获取的卵母细胞数量的分布情况。由于获取的卵母细胞数量为计数数据(count data)，通常可考虑Poisson分布或负二项分布，如图1所示，获卵数显然更符合负二项分布。本实施例选择负二项回归来构建统计模型，预测指标的选择采用修剪的前进法和30％holdback验证，利用软件JMP Pro v.14，建立预测模型，将上述669个患者组成的数据集随机分为两部分，一部分作为训练集(468个数据，70％)，另一部分作为验证集(201个数据，30％)。
首先，在训练集中建模，并在验证集中验证模型效果。预测模型的选择主要根据验证集中的负对数似然值，验证集中的负对数似然值越低，提示模型越优。
包括4个变量时，缩放的-Log L(β)不再下降，因此log[ΔINHB]、log[基础AMH]、年龄和基础FSH 4个变量最终根据其重要性包括在模型中。此时该预测模型中各变量的参数估计结果如表2所示，表2中进一步显示了各参数的95％置信区间。
表2预测模型的参数估计结果
Figure PCTCN2022078998-appb-000002
表3模型在训练集和验证集的性能
Figure PCTCN2022078998-appb-000003
基于上述方法，在本实施例中确认了如下公式一。
ln(NROs)＝a+b*年龄+c*FSH+d*ln[AMH]+f*ln[ΔINHB](公式一)
其中NROs表示成熟卵母细胞数量；年龄表示受试者年龄；FSH表示受试者促排卵治疗前的基础卵泡刺激素水平；AMH表示受试者促排卵治疗前的基础抗缪勒氏管激素水平；ΔINHB表示受试者促排卵治疗过程中早期的抑制素B水平动态变化。
在一个具体的实施方式中，AMH是指受试者在促排卵治疗前月经期任 意时间点静脉血中的抗缪勒氏管激素浓度。FSH是指女性受试者促排卵治疗前月经第2天的静脉血中的卵泡刺激素浓度。ΔΔ静脉血是指女性受试者接受GnRH拮抗剂方案促排卵治疗过程中月经第6天的血清抑制素B浓度与女性受试者月经第2天的静脉血中的抑制素B浓度的差值。
在上述公式(一)中，a选自0.0250603～1.1726555中的任意数值，a优选为0.5988579；
b选自-0.021215～-0.000214中的任意数值，b优选为-0.010715；
c选自-0.031133～0.0043087中的任意数值，c优选为-0.013412；
d选自0.151584～0.2904983中的任意数值，d优选为0.2210412；
f选自0.2445264～0.3871042中的任意数值，f优选为0.3158153。
利用上述方法针对训练集和验证集构建的模型的预测效果如表3、图2和图3所示。图2和图3中，横坐标显示利用模型预测的NROs，即预测的该受试者进行标准拮抗剂方案促排卵，其获得的卵母细胞数量，纵坐标显示该受试者的实际检测到的获取的卵母细胞数量，可见上述构建的模型在训练集和验证集中均获得良好的预测效果，预测的数据与实际检测的数吻合度高。
为了验证系统的准确性，我们在相同的人群中将本发明的模型与CN201910780793.6中描述的模型进行了比较。结果显示，本发明的模型在增加ΔINHB后，反映活化的卵泡生长，虽然模型本发明的模型中没有包含AFC，但模型中的广义R2在训练集和验证集中分别从0.49和0.52显著增加到0.61和0.62。由此可见，本发明的模型更准确，性能更优，与CN201910780793.6中描述的模型相比，散点分布更接近对角线，尤其是预测的正常卵巢反应者(预测≤15个卵母细胞)。总之，与有数据筛选的CN201910780793.6中描述的模型相比，即使没有排除诊断为PCOS的患者，本发明模型的性能仍然更优，如果排除PCOS等卵巢反应异常的病例后，模型效果会更好，表明增加ΔINHB有助于更好地预测NROs。另外，本发明的模型构建过程中，没有对使用的669个患者进行筛选，即没有制定严格的纳入标准和排除标准，因此本发明的模型具有更好的适应性。
在第二种模型中，针对上述669个患者的数据，结局变量与第一种模型一致，都是获卵数，数据也相同，因此还是使用负二项回归进行分析。预测指标的选择采用修剪的前进法和30％holdback验证，利用软件JMP Pro v.14， 建立预测模型，将上述669个患者组成的数据集随机分为两部分，一部分作为训练集(468个数据，70％)，另一部分作为验证集(201个数据，30％)。
首先，在训练集中建模，并在验证集中验证模型效果。预测模型的选择主要根据验证集中的负对数似然值，验证集中的负对数似然值越低，提示模型越优。
当包括4个变量时，缩放的-Log L(β)不再下降，因此log[ΔINHB]、log[基础AMH]、年龄和基础AFC这4个变量最终根据其重要性包括在模型中。血清ΔINHB的主要影响可以解释58.9％的观察到的NROs，其次是基础AMH水平，解释了31.6％的结果变量，以及对数基础AFC水平和年龄，分别解释了4.3％和0.4％。此时该预测模型中各变量的参数估计结果如表4所示，表4中进一步显示了各参数的95％置信区间。
基于上述方法，在本实施例中确认了如下公式二。
ln(NROs)＝g+h*年龄+i*ln[基础AMH]+j*ln[ΔINHB]+k*ln[AFC](公式二)
其中NROs表示成熟卵母细胞数量；年龄表示受试者年龄；AFC表示受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数；AMH表示受试者促排卵治疗前的基础抗缪勒氏管激素水平；ΔINHB表示受试者促排卵治疗过程中早期的抑制素B水平动态变化。
在一个具体的实施方式中，AMH是指受试者在促排卵治疗前月经期任意时间点静脉血中的抗缪勒氏管激素浓度。AFC是指女性受试者促排卵治疗前月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数。ΔINHB是指女性受试者接受GnRH拮抗剂方案促排卵治疗过程中月经第6天的血清抑制素B浓度与女性受试者月经第2天的静脉血中的抑制素B浓度的差值。
在上述公式(二)中，g选自-0.447201～0.9161863中的任意数值，优选为0.2344927；
h选自-0.017165～0.0039328中的任意数值，优选为-0.006616；
i选自0.1318094～0.3113979中的任意数值，优选为0.2216036；
j选自0.1901643～0.3850919中的任意数值，优选为0.2876281；
k选自0.0541966～0.2338079中的任意数值，优选为0.1440023。
表4预测模型的参数估计结果
Figure PCTCN2022078998-appb-000004
表5模型在训练集和验证集的性能
Figure PCTCN2022078998-appb-000005
利用上述方法针对训练集和验证集构建的模型的预测效果如表5、图4和图5所示。图5中，横坐标显示利用模型预测的NROs，即预测的该受试者进行标准拮抗剂方案促排卵，其获得的卵母细胞数量，纵坐标显示该受试者的实际检测到的获取的卵母细胞数量，可见上述构建的模型在训练集和验证集中均获得良好的预测效果，预测的数据与实际检测的数吻合度高。
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 (20)

  1. 一种用于预测受试者的成熟卵母细胞数量的系统，其包括：
    数据采集模块，其用于获取受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据；以及
    成熟卵母细胞数量计算模块，其用于对数据采集模块中的获取的上述数据进行计算，从而计算出受试者在促排卵周期获得的成熟卵母细胞数量(NROs)。
  2. 根据权利要求1所述的系统，其中，
    所述受试者是将要接受标准促排卵治疗的受试者，所述受试者的成熟卵母细胞数量是在受试者接受促排卵治疗后卵巢刺激过程中获得的直径在18毫米以上的成熟卵母细胞数量。
  3. 根据权利要求1或2所述的系统，其中，
    在成熟卵母细胞数量计算模块中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于计算受试者成熟卵母细胞数量(NROs)的公式。
  4. 根据权利要求1～3中任一项所述的系统，其中，
    在数据采集模块中，收集的基础抗缪勒氏管激素(AMH)水平是指受试者在促排卵治疗前月经期任意时间点静脉血中的抗缪勒氏管激素浓度。
  5. 根据权利要求1～4中任一项所述的系统，其中，
    在数据采集模块中，收集的基础卵泡刺激素(FSH)水平是指女性受试者促排卵治疗前月经第2天的静脉血中的卵泡刺激素浓度。
  6. 根据权利要求1～5中任一项所述的系统，其中，
    在数据采集模块中，收集的基础窦卵泡计数(AFC)是指阴道B超计数女性受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数。
  7. 根据权利要求1～6中任一项所述的系统，其中，
    在数据采集模块中，收集的抑制素B水平动态变化(ΔINHB)是指促排卵 治疗早期的抑制素B水平动态变化(ΔINHB)，优选为女性受试者接受GnRH拮抗剂方案促排卵治疗周期月经第6天的血清抑制素B浓度与月经第2天的静脉血中的抑制素B浓度的差值。
  8. 根据权利要求3～6中任一项所述的系统，其中，
    在成熟卵母细胞数量计算模块中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于预测受试者成熟卵母细胞数量(NROs)的公式是将现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据利用负二项分布拟合得到的计算公式；
    该公式能够利用所述数据采集模块采集的受试者的年龄数据、受试者的基础抗缪勒氏管激素(AMH)水平数据、受试者的基础卵泡刺激素(FSH)水平数据或基础窦卵泡计数(AFC)数据和受试者的抑制素B水平动态变化(ΔINHB)数据来计算该受试者获得的成熟卵母细胞数量(NROs)。
  9. 根据权利要求8所述的系统，其中，
    当数据采集模块收集的是基础卵泡刺激素(FSH)水平时，所述公式为如下公式一：
    ln(NROs)＝a+b*年龄+c*基础FSH+d*ln[基础AMH]+f*ln[ΔINHB](公式一)；
    其中，a选自0.0250603～1.1726555中的任意数值，优选为0.5988579；
    b选自-0.021215～-0.000214中的任意数值，优选为-0.010715；
    c选自-0.031133～0.0043087中的任意数值，优选为-0.013412；
    d选自0.151584～0.2904983中的任意数值，优选为0.2210412；
    f选自0.2445264～0.3871042中的任意数值，优选为0.3158153。
  10. 根据权利要求8所述的系统，其中，
    当数据采集模块收集的是基础窦卵泡计数(AFC)时，所述公式为如下公式二：
    ln(NROs)＝g+h*年龄+i*ln[基础AMH]+j*ln[ΔINHB]+k*ln[AFC](公式 二)；
    其中，g选自-0.447201～0.9161863中的任意数值，优选为0.2344927；
    h选自-0.017165～0.0039328中的任意数值，优选为-0.006616；
    i选自0.1318094～0.3113979中的任意数值，优选为0.2216036；
    j选自0.1901643～0.3850919中的任意数值，优选为0.2876281；
    k选自0.0541966～0.2338079中的任意数值，优选为0.1440023。
  11. 一种用于预测受试者的成熟卵母细胞数量的方法，其包括：
    数据采集步骤，其获取受试者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据；以及
    成熟卵母细胞数量计算步骤，其对数据采集步骤中的获取的上述数据进行计算，从而计算出受试者的获取的成熟卵母细胞数量(NROs)。
  12. 根据权利要求11所述的方法，其中，
    所述受试者是将要接受标准促排卵治疗的受试者，所述受试者的成熟卵母细胞数量是在受试者接受促排卵治疗后卵巢刺激过程中获得的卵泡直径大于18毫米的成熟卵母细胞数量。
  13. 根据权利要求11或12所述的方法，其中，
    在成熟卵母细胞数量计算步骤中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于计算受试者成熟卵母细胞数量(NROs)的公式。
  14. 根据权利要求11～13中任一项所述的方法，其中，
    在数据采集步骤中，收集的基础抗缪勒氏管激素(AMH)水平是指受试者在促排卵治疗前月经期任意时间点静脉血中的抗缪勒氏管激素浓度。
  15. 根据权利要求11～14中任一项所述的方法，其中，
    在数据采集步骤中，收集的基础卵泡刺激素(FSH)水平是指女性受试者促排卵治疗前月经第2天的静脉血中的卵泡刺激素浓度。
  16. 根据权利要求11～15中任一项所述的方法，其中，
    在数据采集步骤中，收集的基础窦卵泡计数(AFC)是指阴道B超计数女 性受试者月经第2天的两个卵巢中直径为2-10mm的所有可见卵泡的个数。
  17. 根据权利要求11～16中任一项所述的方法，其中，
    在数据采集步骤中，收集的抑制素B水平动态变化(ΔINHB)是指促排卵治疗早期的抑制素B水平动态变化(ΔINHB)，优选为女性受试者接受GnRH拮抗剂方案促排卵治疗促排卵周期月经第6天的血清抑制素B浓度与女性受试者促排卵周期月经第2天的静脉血中的抑制素B浓度的差值。
  18. 根据权利要求13～16中任一项所述的方法，其中，
    在成熟卵母细胞数量计算步骤中，预先存储有基于现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据拟合而成的用于预测受试者成熟卵母细胞数量(NROs)的公式是将现有数据库中接受过标准GnRH拮抗剂方案促排卵治疗患者的年龄、基础抗缪勒氏管激素(AMH)水平、基础卵泡刺激素(FSH)水平或基础窦卵泡计数(AFC)、抑制素B水平动态变化(ΔINHB)的数据利用负二项分布拟合得到的计算公式；
    该公式能够利用所述数据采集步骤采集的受试者的年龄数据、受试者的基础抗缪勒氏管激素(AMH)水平数据、受试者的基础卵泡刺激素(FSH)水平数据或基础窦卵泡计数(AFC)数据和受试者的抑制素B水平动态变化(ΔINHB)数据来计算该受试者获得的成熟卵母细胞数量(NROs)。
  19. 根据权利要求18所述的方法，其中，
    当数据采集步骤收集的是基础卵泡刺激素(FSH)水平时，所述公式为如下公式一：
    ln(NROs)＝a+b*年龄+c*基础FSH+d*ln[基础AMH]+f*ln[ΔINHB](公式一)；
    其中，a选自0.0250603～1.1726555中的任意数值，优选为0.5988579；
    b选自-0.021215～-0.000214中的任意数值，优选为-0.010715；
    c选自-0.031133～0.0043087中的任意数值，优选为-0.013412；
    d选自0.151584～0.2904983中的任意数值，优选为0.2210412；
    f选自0.2445264～0.3871042中的任意数值，优选为0.3158153。
  20. 根据权利要求18所述的方法，其中，
    当数据采集步骤收集的是基础窦卵泡计数(AFC)时，所述公式为如下公式二：
    ln(NROs)＝g+h*年龄+i*ln[基础AMH]+j*ln[ΔINHB]+k*ln[AFC](公式二)；
    其中，g选自-0.447201～0.9161863中的任意数值，优选为0.2344927；
    h选自-0.017165～0.0039328中的任意数值，优选为-0.006616；
    i选自0.1318094～0.3113979中的任意数值，优选为0.2216036；
    j选自0.1901643～0.3850919中的任意数值，优选为0.2876281；
    k选自0.0541966～0.2338079中的任意数值，优选为0.1440023。
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