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WO2010061613A1 - Procédé, système et kit d'assistance à la grossesse - Google Patents

Procédé, système et kit d'assistance à la grossesse Download PDF

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Publication number
WO2010061613A1
WO2010061613A1 PCT/JP2009/006399 JP2009006399W WO2010061613A1 WO 2010061613 A1 WO2010061613 A1 WO 2010061613A1 JP 2009006399 W JP2009006399 W JP 2009006399W WO 2010061613 A1 WO2010061613 A1 WO 2010061613A1
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WIPO (PCT)
Prior art keywords
time
concentration
ovulation
memory
hormone
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English (en)
Japanese (ja)
Inventor
穴沢隆
藤田毅
矢澤義昭
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Hitachi Ltd
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Hitachi Ltd
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Priority to JP2010540378A priority Critical patent/JP5308452B2/ja
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/76—Human chorionic gonadotropin including luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]

Definitions

  • the present invention relates to an analysis system and method for analyzing biological substances such as nucleic acids, proteins and microorganisms contained in biological samples such as blood, urine and saliva.
  • the present invention relates to a monitoring method, a monitoring system, and a test kit for analyzing luteinizing hormone contained in urine for the purpose of estimating ovulation time for supporting pregnancy of women.
  • ⁇ Infertility treatment mainly includes (1) timing therapy, (2) hormone therapy, (3) artificial insemination, and (4) in vitro fertilization, which are generally performed while stepping up in this order. For example, perform (1) for the first 3 months, and if you do not become pregnant at this stage, perform (2) while using (1) for the next 3 months.
  • (1) to (3) are also called general fertility treatments, and (4) is also called advanced fertility treatments.
  • the statistical proportion of successful pregnancy steps is 14% for (1), 33% for (2), and (3) Is 19% and (4) is around 34%.
  • Timing therapy is a method of estimating the date of ovulation based on the fact that the period before and after the date of ovulation is most likely to become pregnant, and adjusting the timing of sex accordingly.
  • (A) is a method that has been known for a long time and is the most popular method, and is performed using a female thermometer.
  • the low temperature period continues, transitions from the low temperature period to the high temperature period after the day of ovulation, and repeats a basal body temperature cycle with a change range of 0.3 to 0.5 ° C that returns to the low temperature period just before the next menstruation. Since the rise in basal body temperature occurs after the day of ovulation, it is too late to wait for the rise in basal body temperature and adjust the timing. For this reason, the individual's basal body temperature cycle is learned several times, and the date of ovulation is estimated based on this. However, in addition to the unstable body temperature measurement itself, the date of ovulation changes depending on the physical condition and the like, and it is said that an error of about ⁇ 3 days is caused in the estimation of the ovulation date.
  • (B) is a method of capturing luteinizing hormone (Luteinizing Hormone, LH) secreted from the pituitary gland in the urine using immunochromatography, which is a simple test device. Since LH release occurs at once, it is called LH surge, and the change in concentration over time shows a mountain profile with a half width of about 24 hours and a base width of about 48 hours in blood and urine. It is known that ovulation is promoted by LH surge, and ovulation occurs in about 36 hours from the start of LH surge and in about 12 hours from LH surge peak.
  • the LH surge peak indicates the peak of the peak profile
  • the LH surge indicates the peak profile itself.
  • the urinary LH test is repeated discretely at intervals of about 24 hours from several days before the expected date of ovulation, and the date of ovulation is estimated based on the obtained signal.
  • the principle of the immunochromatography method is as follows.
  • the primary antibody (immobilized antibody) against the antigen to be tested (LH in the case of this test) is placed on the permeable membrane such as nitrocellulose stored inside the container of the handy strip-shaped test device in advance.
  • (C) is a method of directly observing the follicle by transvaginal ultrasound diagnosis.
  • the follicle size is known to be 18-23 mm on the day before ovulation and 21-27 mm just before ovulation.
  • (B) is the main timing therapy that can be easily performed at home.
  • LH simple test kits are sold not only for medical use but also for general use at pharmacies.
  • Non-Patent Document 3 An attempt is made to estimate the date of ovulation by LH test by conducting serum LH test and follicular ultrasonography for a large number of female subjects. While many other documents perform the same inspection at intervals of 24 hours, Non-Patent Document 3 performs the same inspection at intervals of 4 hours, and thus is one of the documents with the highest time accuracy.
  • the LH test is a highly accurate quantitative measurement by radioimmunoassay. From these, this document is considered to provide the most accurate knowledge.
  • the time course of serum LH concentration is roughly a Gaussian profile with a baseline of 20 ⁇ mIU / ml, a peak height of 200 ⁇ mIU / ml, and a standard deviation of about 14 hours, 27 hours and 20 minutes after the start of the LH surge, and It is concluded that ovulation occurs 10 hours after the LH surge peak time.
  • the LH surge start time is defined as the time when the serum LH concentration exceeds the threshold of 60 ⁇ mIU / ml. Based on these findings, the ovulation date can be estimated from the LH test results.
  • Non-patent document 4 attempts to estimate the date of ovulation by urinary LH test. It is considered that the time change of LH concentration in serum and urine is different in baseline and peak height, but the profile is almost similar and the time lag is about several hours. Non-Patent Document 4 reports that this time lag is about 2 hours. In addition, it is considered that the time change profile of the LH concentration changes depending not only on the type of sample but also on the sample pretreatment method, the quantitative measurement method of the LH concentration, the difference in the population of sample collection targets, and the like.
  • Non-Patent Document 5 when a urine LH test was performed on 26 female subjects using a commercially available kit Ovuquick (Quidel), all cases were positively detected. Among these, 19 cases (73%) were positively detected in the range of 0-24 hours preceding the ovulation time, and 24 cases (92%) were positively detected in 0-48 hours. The kit has been shown to be effective in estimating ovulation dates.
  • Non-Patent Document 6 five commercial kits ClearPlan Easy One-Step (Unipath Diagnostics), OvuKit Self-Test (Quidel), OvuQuick Self-Test (Quidel), Sure Step Ovulation Predicator (Applied Biotech), The urinary LH test by EZ-LH One Step Ovulation Kit (Norwell Technologies) and radioimmunoassay, which is a high-precision quantitative measurement, are compared for 11 female subjects.
  • LH surge peak concentrations varied from 13.5 to 73.0 ⁇ mIU / ml, ovulation occurred within 24 hours from the peak time in 8 cases, and ovulation occurred in 24 to 48 hours from the peak time in 2 cases.
  • the positive detection lower limit concentration of each kit varies in the range of 25.5-48.7 mIU / ml
  • the most sensitive kit ClearPlan Easy One-Step is 6 cases
  • the least sensitive kit EZ-LH One Step Ovulation Kit is Three cases were positively detected.
  • a concentration range bordering between positive and negative was observed in each kit.
  • menstrually related hormones such as estrogen, progesterone, or LH are quantitatively measured at 24-hour intervals, and when it is confirmed that the quantitative concentration exceeds a preset concentration threshold, the ovulation period, ovulation It proposes a method to estimate the day, the date of menstruation, the expected date of delivery, etc.
  • LH concentration quantitative value when it is confirmed that the LH concentration quantitative value has exceeded a preset concentration threshold, or when it has been confirmed that it has passed the peak of the concentration profile, it is preset at each time point.
  • Patent Document 2 estrogen and progesterone are quantitatively measured at 24-hour intervals, points are given based on preset criteria for each concentration quantitative value and its rate of change, and each cumulative score is preset. When it is confirmed that the cumulative score threshold has been exceeded, a method for estimating the date of each time point as the start date and the end date of the fertile period is proposed. Furthermore, Patent Document 3 proposes a simple quantitative test kit that performs positive or negative quantitative measurement. In addition, according to Non-Patent Document 7, the peak of the estradiol concentration change profile exists about 24 hours before the peak of the LH surge, and ovulation occurs about 34 hours after the peak time of the estradiol concentration change profile. Are known.
  • Timing therapy that can be easily done at home without going to the hospital is based on the urinary LH simple test, but there are 400,000 couples who are concerned about infertility but have not been to the hospital, It is important to disseminate to wider layers. For this purpose, it is effective to realize early and highly accurate ovulation time estimation as a timing therapy that can be easily performed at home without performing follicle size measurement that cannot be performed without going to a hospital.
  • the time interval of LH inspection is set to 24 hours.
  • the interval between the LH surge start time and the ovulation time is ⁇ tso
  • the interval between the LH surge peak time and the ovulation time is ⁇ tpo.
  • the unit of time is hours (hours) unless otherwise specified, and rounded to the nearest decimal place.
  • the unit of LH concentration is expressed as mIU / ml unless otherwise specified, and is rounded off after the decimal point.
  • Patent document 1 corresponds.
  • Patent Document 2 a cumulative score threshold is used instead of a simple density threshold, but since the estimation is performed based on the threshold excess time at the threshold excess time, the performance is essentially the same.
  • a high-precision quantitative measurement device is placed at home without using a simple LH inspection kit and LH inspection is performed. This involves problems such as device cost, space for installing the device at home, and labor for operating the device.
  • the LH surge peak excess time tn is set as the estimated LH surge peak time tep.
  • the time tn when the ovulation time is estimated may be immediately before the actual ovulation time to (tn to to) or may pass the ovulation time to (to ⁇ tn). Is unsuitable.
  • the threshold excess time tm m is any one of 1, 2, 3,...) Is later than the actual LH concentration threshold time tt (tt ⁇ tm).
  • the LH surge start excess time tm is later than the actual LH surge start time ts (ts ⁇ tm).
  • the LH concentration threshold excess time tm may vary in the range of tt ⁇ tm ⁇ tt + 24 and ts ⁇ tm ⁇ ts + 24, so that tep and tes, and teo based on them, are at least 24 hours. Variation. That is, the ovulation time is estimated with a resolution that is coarser than the daily unit. This occurs because the presence or absence of the LH surge is only quantitatively determined without considering the profile of the LH surge. Even when tep and tes are not written, the same performance is obtained when ovulation time is estimated based on tn and tm.
  • the performance is equivalent to the above case.
  • the LH simple test kit has low sensitivity and Cd> Cs, or high sensitivity and Cd ⁇ Cs.
  • the time tm when the LH surge start can be recognized (the time when the positive detection is first obtained) is further delayed than when the LH test is quantitative, and the sample collection time and LH surge timing This increases the chance that LH surge peaks cannot be positively detected.
  • the LH surge peak cannot be detected positively at all, and the ovulation time cannot be estimated.
  • the LH simple test kit becomes highly sensitive, the chance of recognizing the start of the LH surge at the baseline stage before the start of the LH surge (tm ⁇ ts) increases, and the ovulation time is estimated with no grounds. descend.
  • the main object of the present invention is to provide a monitoring method, a monitoring system, and a test kit for pregnancy support, which solve each of the above-mentioned problems and realize an early and highly accurate estimation of the LH surge peak time and the ovulation time. To do.
  • the present invention is a method for monitoring a fertile state, the step of bringing a biological sample into contact with a detection device, detecting the hormone concentration in the biological sample and storing it in a memory, and the collection time of the biological sample And the hormone concentration to be measured in the collected biological sample is detected to exceed a hormone concentration threshold value stored in advance in the memory, and the hormone stored and set in the memory is detected.
  • the present invention enables early and highly accurate ovulation time estimation by the LH test, and therefore enables highly reliable timing therapy that can be easily performed at home without going to the hospital.
  • many couples who want a natural pregnancy especially those who are concerned about infertility and feel resistance to going to the hospital, have used this method, resulting in many couples becoming pregnant early, The number of births is expected to improve.
  • for couples who do not readily become pregnant even if the present invention is used notice early on the possibility that some kind of infertility treatment is necessary, and by prompting hospital visits, as a result, early pregnancy results, The number of births is expected to improve.
  • the present invention is expected to save many couples who want to become pregnant and provide a solution to the problem of declining birthrate.
  • concentration in FIG. The figure which shows the relationship between the standard time of # 1 of Table 2, and LH density
  • FIG. 2 is a diagram showing an approximate LH concentration time variation profile derived from Method 1 from FIG.
  • FIG. 3 is a diagram showing an approximate LH concentration time variation profile derived from FIG.
  • FIG. 6 is a diagram showing a performance comparison of LH surge peak time estimation between the present methods 1 and 2 and the conventional method in Example 1 of the present invention.
  • FIG. 6 is a diagram showing an approximate LH concentration time change profile derived by the present method 1 from the relationship between the standard time of Non-Patent Document 4 and the LH concentration in Example 2 of the present invention.
  • FIG. 6 is a diagram showing an improvement in performance of LH surge peak time estimation by renewal or improvement of an approximate LH concentration time change profile in Example 2.
  • FIG. 5 is a schematic diagram when an optical sensor chip is used in Example 3.
  • FIG. 4 is a schematic diagram of a configuration and chemical reaction of an inspection device in Example 3.
  • FIG. 4 is a schematic diagram of the configuration and chemical reaction of an inspection device and an external measurement device in Example 3.
  • the flowchart which shows an example of the estimation process at the time of ovulation of this invention.
  • a quantitative LH test is performed as a timing therapy that can be easily performed at home without going to the hospital.
  • the time interval of the LH inspection is arbitrary, the case of 24 hours will be described as a typical example.
  • FIG. 27 shows an example of the flow of ovulation estimation processing according to the present invention.
  • the biological sample is brought into contact with a detection device, the hormone concentration in the biological sample is detected and stored in a memory (S01 to S03), and the collection time of the biological sample is stored in the memory. And detecting that the concentration of the hormone to be measured in the collected biological sample exceeds a threshold value of the hormone concentration stored in advance in the memory, and the concentration time change of the hormone concentration stored and set in the memory.
  • the algorithm of the estimation process at the time of ovulation in the present invention is as follows. Time-discrete quantitative value of LH concentration of a certain population shown in literature etc., or time-discrete quantification of LH concentration acquired for a specific population or individual as a true LH concentration time change profile TP (T)
  • the values are TP (T1), TP (T2), TP (T3), and so on. That is, to simplify the explanation, it is assumed that TP (T1), TP (T2), TP (T3), ... have no error from the true value.
  • T is a standard time standardized so that the LH surge peak time becomes 0, and represents only a part of one physiological cycle.
  • TP (T1), TP (T2), TP (T3), ... are statistical values such as the mean value in the population, whereas C (t1), C (t2), C ( t3), ... are non-statistical values determined for each physiological cycle of each subject.
  • the time axis is converted from the standard time T to the sample collection time t.
  • the least square method may be used, or AP (t) may pass a specific quantitative value, for example, C (tm).
  • fitting with correction of coefficients other than the time in the function may be performed.
  • Example 1 of the present invention an example will be described in which the estimated ovulation time teo is acquired by fixing the approximate LH concentration time change profile AP (T) based on the flow of FIG.
  • T approximate LH concentration time change profile
  • Non-Patent Document 3 unlike many other documents, serum LH test and follicular ultrasonography are performed at 4-hour intervals, so high time accuracy of about 4 hours can be obtained for TP (T).
  • T11 144.
  • T1 -96
  • T2 -72
  • T3 -48
  • T4 -24
  • T8 72
  • T9 96
  • T10 120
  • T11 144.
  • TP (T) be the black circle plot and the solid broken line connecting them.
  • T5 0, TP (T) shows an LH surge peak with a maximum value of 200 ⁇ 89 ⁇ mIU / ml.
  • the standard time is set to a random value -96 + R (# 1) in the range of -96 ⁇ T ⁇ ⁇ 72, and the random value RP between the above broken line 1 and the broken line 2 at this standard time -96 + R (# 1)
  • the LH surge peak in Table 3 is used. Estimate time tp and compare their performance. At this time, among the information in Table 2, when the time when the LH concentration quantitative value first exceeds the concentration threshold Ct is tm (m is any of 1, 2, 3, ...), t1, t2, ⁇ ⁇ Use only tm information.
  • the information in Table 2 is data that is randomly distributed according to the actual situation both in the time axis direction and in the concentration axis direction, so it is considered appropriate for comparing the ovulation time estimation methods.
  • the LH surge peak time is estimated by a conventional method with quantitative LH inspection.
  • the correct LH surge peak time tp is recorded, and at the same time, the deviation from each estimated LH surge peak time tep.
  • a cross is indicated in the column.
  • the concentration threshold Ct is often unknown or the concentration threshold Ct is often deviated from the optimum value 60. Even if the LH simple test kit is the same product, the concentration threshold Ct varies depending on individual differences. For example, if the concentration threshold Ct varies between 30 and 120, tep varies between the threshold 30 AV and SD in Table 4 and the threshold 120 AV and SD, so the LH surge peak time estimation performance is quantitative. It is inferior to some conventional methods.
  • the LH surge peak time tep is estimated according to the present invention.
  • AP (T) 200 does not have to be a condition.
  • This AP (T) is shown by a solid line in FIG. 13 together with the black circle plot and error bar in FIG.
  • Fig. 14 the time axis is converted from the standard time T to the sample collection time t, the data of # 7 in Table 2 is indicated by a rhombus plot, and AP (t) is indicated by a solid line. Add arrows to the first three square plots used for fitting.
  • the approximate LH concentration time change profile AP (T) is expressed by a line segment.
  • AP (T) 5.67 * T + 200 (0 ⁇ AP (T) ⁇ 200), which is indicated by a solid line in FIG. 15 together with the black circle plot and error bar in FIG.
  • the time axis is converted from the standard time T to the sample collection time t, the data of # 7 in Table 2 is indicated by a rhombus plot, and AP (t) is indicated by a solid line.
  • Table 5 The results of similar estimations for all cases # 1 to # 10 are summarized in Table 5 as “Method 2”. As in Table 4, the number of deviations, tp, AV, SD, and x are also shown.
  • FIG. 17 shows the frequency distribution of 100 deviations according to each method.
  • the upper part of Fig. 17 shows the conventional method (threshold 30) as a black triangle plot, the conventional method (threshold 60) as a black circle plot, and the conventional method (threshold 120) as a black square plot.
  • the lower part of Fig. 17 shows this method 1 as a round plot. This method 2 is indicated by a white triangle plot.
  • the threshold 60 is optimal, and the LH surge peak time can be estimated with an accuracy of ⁇ 14 ⁇ 12 hours 14 hours before the average.
  • the value of 14 is a value determined by TP (T), Ct, and the time interval of sample collection, and can be derived by the above analysis.
  • this method is another means for solving the problems of the present invention.
  • this method does not change the standard deviation of the deviation, so the performance is lower than Method 1 and Method 2.
  • the LH inspection does not have quantification, it is difficult to apply this method because the threshold value varies.
  • Method 1 and Method 2 have almost the same performance, and the deviation and its variation are greatly reduced compared to the conventional method (threshold value 60).
  • Example 2 will be described.
  • the approximate LH concentration time variation profile AP (T) was fixed and the performance evaluation of ovulation time estimation was performed.
  • AP based on the LH test results of individual physiological cycles of individual subjects The performance of ovulation time estimation is improved by renewing or improving T).
  • Non-Patent Document 4 attempts to estimate the date of ovulation by LH test by conducting urinary LH test and follicular ultrasonography on a large number of female subjects.
  • the main cause is considered to be that the sample has changed from serum to urine, but there are other differences in conditions such as the sample pretreatment method, the LH concentration quantitative measurement method, and the sample collection target population.
  • Example 1 is a comparison between the conventional method and the present method with the conditions fixed without considering these differences, but the comparison result is considered to be effective under other conditions.
  • the ovulation time was estimated by this method 1 for 5 cases # 6 to # 10 using this AP (T) and Cs, the deviation was 5 ⁇ 8.
  • Non-Patent Document 4 there is a significant improvement in ovulation time estimation.
  • the second physiological cycle is over and only the LH concentration quantitative values of # 1 and # 2 are obtained.
  • the method of renewing and improving AP (T) shown in this embodiment is an example, and the same effect can be obtained by other methods.
  • LH concentration quantification means including time measurement means is required.
  • an immunoassay apparatus for clinical tests may be used as a high-precision quantitative measurement method, it is not realistic in terms of apparatus cost and installation space to perform daily tests at home.
  • devices that automatically read optically and quantify the substances to be tested instead of visually reading the results of various test kits using immunochromatography, devices that automatically read optically and quantify the substances to be tested have been developed by Roche Diagnostics Co., Ltd., Otsuka Electronics ( Etc.) are sold for in-situ inspection (POCT).
  • the simple quantitative inspection kit proposed in Patent Document 3 solves the above-described problems of quantitative accuracy, device size, and device cost, and is suitable for implementation of the present invention.
  • the effect of the present invention is further enhanced by improving the kit of Patent Document 3.
  • FIG. 20 shows a schematic diagram of the simple quantitative inspection kit and system of the present invention.
  • An external measurement device such as the reader 202 or the personal computer 203 includes at least memories 205 and 208 and calculation units 206 and 209, and the results calculated by the method of the present invention using the inspection device 201 are displayed on the display units 204 and 207.
  • FIG. 21 is a schematic diagram of the case where an optical sensor chip is used, in which the color reaction of the immunochromatography method is switched to a luminescent reaction, and an RFID equipped with a photosensor in the luminescent reaction part on the permeable membrane inside the container of the inspection device 201 A chip (light sensor chip) is installed and the emission intensity is measured.
  • FIG. 21 is a schematic diagram of the case where an optical sensor chip is used, in which the color reaction of the immunochromatography method is switched to a luminescent reaction, and an RFID equipped with a photosensor in the luminescent reaction part on the permeable membrane inside the container of the inspection device 201 A chip (light sensor chip
  • the inspection device 22 schematically shows the flow of the substance to be inspected, the flow and localization of various reagents, and the luminescence reaction on the permeable membrane in the inspection device 201.
  • nitrocellulose is used for the osmotic membrane, but other materials may be used.
  • the immobilized antibody is immobilized in the test part that becomes the luminescence reaction part, the photosensor chip is arranged at this position, and the photosensor chip is also arranged in the blank part as a reference in the vicinity thereof.
  • the enzyme-labeled antibody is held in a dry state in the specimen absorption part (urine absorption part) on the left end side of the osmosis membrane.
  • the antigen (LH) which is the test substance in the sample
  • the enzyme-labeled antibody binds to the enzyme-labeled antibody, and at the same time, through the osmotic membrane toward the right end by capillary action.
  • the antigen also binds to the immobilized antibody, a sandwich complex of the immobilized antibody-antigen-enzyme labeled antibody is formed in the test part.
  • the enzyme-labeled antibody that does not form a sandwich complex passes through the test part and is absorbed by the solution absorption part.
  • Luminescence intensity measurement has a wider linear response range with respect to the concentration of the test target substance than that of color intensity measurement, and therefore has excellent sensitivity and dynamic range for the determination of the test target substance.
  • FIG. 23 shows the results of a calibration curve obtained by quantitative measurement of hCG, which is a pregnancy test marker, instead of LH as the test object by this method.
  • the horizontal axis represents the hCG concentration
  • the vertical axis represents the emission intensity.
  • the light emission intensity is obtained by integrating the output difference between the test part and the blank part for a certain period of time.
  • the hCG concentration of 10 0 to 10 1 ng / ml is a transition region from negative to positive, and the detection lower limit concentration exists in this concentration range.
  • the inspection device has a light shielding structure, and adverse effects due to ambient light can be avoided. There is no window for viewing from the outside of the container of the inspection device.
  • the inspection device is in a sealed state, it is possible to prevent the attached urine from being contaminated to the outside. Since the RFID chip (photosensor chip) is supplied with driving power wirelessly by a reader 212 outside the inspection device as shown in FIG. 21B, the inspection device and the optical sensor chip do not have a power source such as a battery. Therefore, the inspection device can be made disposable by suppressing the unit price by mass production of the optical sensor chip and reducing the manufacturing cost of the inspection device.
  • the inspection device 211 is connected to the reader 212 as shown in FIG.
  • the reader 212 is equipped with a battery as a power source.
  • the reader is not disposable, but is used for multiple inspections.
  • the reader 212 wirelessly feeds and controls the optical sensor chip 211 and reads the optical sensor chip ID and emission intensity data. That is, the inspection device and the reader are not connected by wire. This also contributes to a reduction in the manufacturing cost of the inspection device and at the same time improves the connection reliability.
  • it is desirable that the reader has a socket structure of the inspection device as shown in FIG. Conversely, there is no worry that the data transfer here will be read by others from a distance.
  • the connected inspection device and the reader can be stored in a small bag such as a cosmetic pouch. This is effective for conducting inspections at places other than home, such as toilets at work.
  • the emission intensity data is stored in a memory mounted on the reader.
  • the predetermined switch on the reader is pressed to transmit the emission intensity data to the external measuring device, here the user.
  • time information it is good to memorize
  • any means such as infrared communication, ZigBee, etc. may be used, but safety is ensured so that it cannot be read by others.
  • the mobile phone is preinstalled with LH concentration analysis software, ovulation time estimation software, and display software, and data necessary for analysis by the software is stored in the memory.
  • the LH concentration analysis software quantifies the LH concentration by analyzing the luminescence intensity data, and the ovulation time estimation software estimates the LH surge start time, LH surge peak time, and ovulation time from the LH concentration quantitative value using a unique algorithm, and the display software Displays the LH concentration quantitative value, estimated ovulation time, etc. on the display as numerical values, tables, graphs, etc.
  • the mobile phone has a function of storing emission intensity data and subsequent processing data. In recent years, most people already own and carry their own mobile phones, so by using the mobile phone as an information processing device for computing and displaying results, the simple quantitative test kit and the entire system can be substantially In addition, the cost can be reduced and the size can be reduced.
  • the information processing apparatus may be a personal computer or a portable information terminal as shown in FIG. 20, or a dedicated information processing apparatus. Further, the connection between the reader and the information processing apparatus may be wired, and the reader and the information processing apparatus may be separate devices as shown in FIG. 20, or may be an integrated structure device. In either case, only the inspection device is disposable for each inspection, and it is desirable that the reader and the information processing apparatus are repeatedly used for a plurality of inspections.
  • the external measuring device may incorporate the optical sensor as shown in FIG. good.
  • a window is provided in the container of the inspection device so that the luminescence reaction can be measured from the outside of the container. If the window is closed with a transparent material such as glass, the sealed state of the container can be maintained.
  • the optical sensor of the external measurement device is connected to the container as shown in FIG. It becomes possible to measure the luminescence reaction in the test part inside the container close to the window.
  • the external measuring device shows only a part near the optical sensor.
  • the external measuring device includes at least a circuit for measuring emission intensity, a storage element for storing emission intensity data and time, and a battery for a power source for driving these. Therefore, the element of the optical sensor does not need to have a wireless communication function. Further, the optical sensor can be used repeatedly without being disposable.
  • the inspection device does not need to incorporate an optical sensor chip, it can be manufactured at a lower cost and is more suitable for disposable use.
  • the information processing apparatus that performs calculation and result display may be built in the external measurement device, or may be connected to the external storage device wirelessly or by wire.
  • Example 4 on the display of an information processing device such as a mobile phone, personal computer, or portable information terminal, the LH concentration quantification result, LH surge start time, LH surge peak time, ovulation time, sex timing suitable for pregnancy ( Estimated results such as the period of pregnancy) and the timing of sex suitable for contraception (contraception period) are displayed.
  • an information processing device such as a mobile phone, personal computer, or portable information terminal
  • FIG. 25 (A) shows an example of the result display of the LH concentration quantitative value on the third day from the start of the LH test. Show the bar graph with the quantitative values of LH concentration on the 1st and 2nd days so that the transition of the LH concentration can be seen at a glance. By changing the color of the LH concentration quantitative value on the third day, it is easy to understand that it is the latest data at the present time.
  • the horizontal axis indicates the number of days counted from the start of the LH test, but may indicate the number of days counted from the start of menstruation or a date such as “10/15”.
  • “October 17th (Friday) at 7:00 am, sample collection day: 3rd day, LH concentration: 72 (mIU / ml)” will be shown together so that the current quantitative LH concentration can be determined. To do.
  • the results may be displayed in a graph or table other than the bar graph. Also, since the LH concentration quantitative value on the third day exceeds the concentration threshold value 60, the message “LH concentration exceeds the threshold value. Do you want to estimate the ovulation time?” Is displayed and the user is asked whether execution is possible.
  • the LH surge peak time is estimated according to Method 1 of Example 1 and the result is shown as FIG. 25 (B).
  • the estimation may be performed according to the method 2 of the first embodiment and other algorithms.
  • the LH concentration quantitative value is shown as a rhombus plot, and for the third day, the color of the plot is changed to make it easy to understand that it is the latest data at the present time.
  • the horizontal axis shows the number of days from the start of the LH test, and each day starts at 7:00 am.
  • the result of fitting a Gaussian distribution, which is an approximate LH concentration time change profile, is displayed, and the peak time is displayed as “estimated LH surge peak time: October 18 (Sat) 4 am”.
  • This time is 69 hours after 7 am (Wednesday), October 15, 2008 (Wednesday), when the LH test starts, and is consistent with the results in Table 5.
  • it is expressed as “estimate LH surge peak 21 hours from now”, “estimate LH surge peak within 24 hours from now”, “estimate LH surge peak 12 to 24 hours from now”. It is also effective to clarify the comparison with the current time of Friday, October 17, 2008 at 7:00 am.
  • the error of the estimated LH surge peak time can be expected, for example, if the error is ⁇ 7 hours, “estimated LH surge peak time: Saturday, October 18 4 ⁇ 7 am” or “estimated LH surge peak time: 10 May 17 (Friday) from 9:00 pm to October 18 (Saturday) at 11:00 am ”.
  • the LH surge start time may be estimated and the result may be displayed.
  • the probability distribution of the ovulation time is a Gaussian with a standard deviation of 5 hours. Since the distribution can be assumed, the probability distribution is displayed so as to overlap with the fitting result of the approximate LH concentration time change profile as shown in FIG.
  • the two Gaussian distributions are color-coded, or one Gaussian distribution region is colored so that they can be easily distinguished from each other. Also, as shown in Fig.
  • the pregnancy possible period and the contraceptive possible period are displayed as shown in FIG.
  • the sperm survival time is 48 hours and the egg survival time is 12 hours
  • this time domain is the fitting result of the approximate LH concentration time change profile and It is displayed overlapping the time region of the estimated ovulation time.
  • the period other than the pregnancy possible period is a contraceptive period
  • Fig. 26 (B) "Contraception possible period:-October 16 (Thursday) 9:00 am, October 19 (Sunday) am 7 o'clock ”is displayed, and this time region is displayed so as to overlap with the fitting result of the approximate LH concentration time change profile and the time region of the estimated ovulation time.
  • the contraceptive period and the estimated ovulation time are displayed in different colors so that they can be easily distinguished from each other.
  • timing therapy can be effectively performed by displaying advice more specifically according to the user's needs.
  • the ovulation time is estimated before ovulation for the purpose of estimating the ovulation time early and with high accuracy, but also using the results of the LH test after ovulation, Therefore, the ovulation time may be estimated by the method of the present invention. Since the latter case uses a larger amount of information for estimation, the accuracy of ovulation time estimation is further improved. This allows you to look back on the past after ovulation, check the transition, evaluate your own judgment and behavior, and improve the probability of pregnancy after the next time by reflecting it in the subsequent judgment and behavior. Become. In addition, displaying the history of the user's LH test results for each menstrual cycle or displaying the history of a plurality of organizing cycles in an overlapping manner can be useful for timing determinations from the next time onward.
  • the LH surge peak time or LH surge start time is estimated from the LH concentration quantitative value, and the ovulation time is estimated based on these times, but the method of the present invention is used for hormones other than LH. May be.
  • estradiol estradiol
  • estradiol is a hormone that is secreted by many women just before ovulation, just like LH.
  • Non-Patent Document 7 it is known that the peak of estradiol concentration change profile exists about 24 hours before the peak of LH surge, and ovulation occurs about 34 hours after the peak time of estradiol concentration change profile. ing.
  • the ovulation time can be estimated earlier than in the case of LH. .
  • a more accurate estimated ovulation time can be derived. It is easy for the user to display the concentration change profiles and estimated ovulation times of a plurality of hormones or to display the integrated estimated ovulation times in an overlapping manner.
  • the sum of probability distributions of ovulation times obtained for each may be used, or a product may be used.
  • an estimation method of ovulation time using basal body temperature may be displayed together with this method. For example, if the changes in basal body temperature and changes in the LH concentration quantitative value for each day are overlaid, and the ovulation time estimated from each or the integrated estimated ovulation time is overlaid, more accurate ovulation time estimation is possible. Become.
  • the present invention provides a test kit and system for hormones such as LH that realizes early and highly accurate ovulation time estimation.

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Abstract

L'invention porte sur un procédé et sur un système qui permettent une estimation très précise de la période de pic de poussée de lutéostimuline et de la période d'ovulation à un stade précoce.  Ledit  procédé comporte : le prélèvement d'échantillons d'urine d'un seul sujet à des intervalles de 24 heures pendant un seul cycle de menstruation ; la détermination de la lutéostimuline (LH) dans les échantillons afin de donner les concentrations de lutéostimuline (valeur quantitative) (diagramme diamant) ; au moment (à 48 heures de l'échantillonnage)où la concentration en lutéostimuline dépasse un seuil de concentration de lutéostimuline prédéterminé (60 mlU/ml), l'ajustement d'une fonction de modification dans le temps de la concentration de lutéostimuline prédéterminée (distribution de Gauss) pour les concentrations de lutéostimuline (valeurs quantitatives) obtenues jusqu'à ce moment (trois diagrammes diamants indiqués par les flèches) à l'aide du procédé des moindres carrés ; l'estimation de la période de pic de la fonction après l'ajustement comme période de pic de poussée de lutéostimuline (à 69 heures de l'échantillonnage) ; et l'estimation de la période d'ovulation en fonction de la période de pic de poussée de lutéostimuline. La ligne en pointillé indique la période correcte de pic de poussée de lutéostimuline (à 75 heures de l'échantillonnage).
PCT/JP2009/006399 2008-11-28 2009-11-26 Procédé, système et kit d'assistance à la grossesse Ceased WO2010061613A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
CN103126728A (zh) * 2013-03-06 2013-06-05 成都大熊猫繁育研究基地 大熊猫正常或延迟排卵的确定方法
CN103185804A (zh) * 2011-12-28 2013-07-03 丁鑫 组合不同灵敏度排卵检测试纸半定量测量lh浓度法
WO2013099376A1 (fr) * 2011-12-26 2013-07-04 国立大学法人福井大学 Marqueur d'ovule mature pour l'utilisation dans la fécondation in vitro et utilisation de ce marqueur
CN108362893A (zh) * 2017-12-31 2018-08-03 深圳市金乐智能健康科技有限公司 一种智能电子检测排卵期的控制方法及系统
CN108362894A (zh) * 2017-12-31 2018-08-03 深圳市金乐智能健康科技有限公司 一种排卵检测方法及装置

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JP2003290230A (ja) * 2002-04-04 2003-10-14 Matsushita Electric Ind Co Ltd 測定装置
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Publication number Priority date Publication date Assignee Title
JPH10115614A (ja) * 1992-08-21 1998-05-06 Unipath Ltd モニタ装置
JP2003290230A (ja) * 2002-04-04 2003-10-14 Matsushita Electric Ind Co Ltd 測定装置
JP2007333695A (ja) * 2006-06-19 2007-12-27 Hitachi Ltd 生体及び化学反応分析キット

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013099376A1 (fr) * 2011-12-26 2013-07-04 国立大学法人福井大学 Marqueur d'ovule mature pour l'utilisation dans la fécondation in vitro et utilisation de ce marqueur
CN103185804A (zh) * 2011-12-28 2013-07-03 丁鑫 组合不同灵敏度排卵检测试纸半定量测量lh浓度法
CN103126728A (zh) * 2013-03-06 2013-06-05 成都大熊猫繁育研究基地 大熊猫正常或延迟排卵的确定方法
CN103126728B (zh) * 2013-03-06 2014-03-19 成都大熊猫繁育研究基地 大熊猫正常或延迟排卵的确定方法
CN108362893A (zh) * 2017-12-31 2018-08-03 深圳市金乐智能健康科技有限公司 一种智能电子检测排卵期的控制方法及系统
CN108362894A (zh) * 2017-12-31 2018-08-03 深圳市金乐智能健康科技有限公司 一种排卵检测方法及装置

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