EP0734531A1 - Procedes et moyens de determination de la periode de fecondation chez une femme - Google Patents

Procedes et moyens de determination de la periode de fecondation chez une femme

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Publication number
EP0734531A1
EP0734531A1 EP95905393A EP95905393A EP0734531A1 EP 0734531 A1 EP0734531 A1 EP 0734531A1 EP 95905393 A EP95905393 A EP 95905393A EP 95905393 A EP95905393 A EP 95905393A EP 0734531 A1 EP0734531 A1 EP 0734531A1
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EP
European Patent Office
Prior art keywords
day
period
hormone
fertile period
fertile
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP95905393A
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German (de)
English (en)
Inventor
Steven C. March
Tzyy-Wen Jeng
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Abbott Laboratories
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Abbott Laboratories
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0734531A1 publication Critical patent/EP0734531A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • G01N33/743—Steroid hormones
    • 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
    • G16H40/00—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices
    • G16H40/60—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices
    • G16H40/63—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices for local operation

Definitions

  • the present invention relates generally to methods and means for determining periodic fertility of a female. More particularly, the present invention utilizes methods and means for determining when the fertile period begins via the evaluation of a series of measurements of urine hormones. The measurements are made with regular assay methods, essentially daily, after the first day of menses and continuing until the end of the fertile period. In addition, the present invention relates to a method for verifying the actual occurrence of ovulation, and therefore, the end of fertile period.
  • the calendar method is based on the determination of the usual length of a woman's menstrual cycle and dividing by two. The presumption is that ovulation occurs approximately in the middle of the cycle. For example, if the woman's normal cycle length is 23-24 days, ovulation is presumed to occur on the 12th day; if the woman's normal cycle length is 40 days, ovulation may be presumed to occur between days 20 and 28. This method only provides a rough estimate of when ovulation may occur and is very difficult to use for most women whose cycle length varies from cycle to cycle.
  • a woman may know approximately when she is ovulating if she experiences a mid-month sharp pain in the lower abdomen, indicating that ovulation is about to, or has just occurred. However, this is not a very reliable sign as this pain can be confused with other pain and is not felt by every woman.
  • the sympto-thermal method increases the indicative value of the calendar method, and is based on the theory that basal body temperature rises discemibly (about 0.4° C) shortly after ovulation has occurred. This phenomenon is related to the production of progesterone by the Graffian follicle. Because ovulation usually occurs around the middle of the menstrual cycle, basal body temperature monitoring is begun at about that time. To detect the increase in temperature, a woman must take her temperature every morning, on waking, at the same time throughout the cycle and record the results, typically as a graph of temperature versus day of cycle. When an appropriately sensitive thermometer is properly used, a distinct increase in basal body temperature should be evident after ovulation has occurred. After recording this information over several months, a woman may be able to predict when ovulation will occur in subsequent cycles. However, as stated above, this method, is unsuitable for women who have irregular cycle length.
  • a fundamental problem is the difficulty in predicting the length of the ongoing menstrual cycle from previous cycles because most women do not have a standardized cycle length for every cycle.
  • each of these methods involves long intervals when users must practice abstinence or use additional contraceptive means.
  • These methods may also involve ambiguity in interpreting the indicator of the beginning of the fertile period, as well as a high probability of method failure, i.e., conception.
  • the conventional sympto-thermal method of contraception involves an abstinence period or risk interval of ten days and has an efficacy (Pearl Index) of 22 pregnancies per 100 women-year of use.
  • J.P. Royston (Biometrics, 38, 397-406, 1982) describes the relationship among basal body temperature, ovulation, and the risk of conception, with special reference to the lifetimes of sperm and egg.
  • Brown et al. (Am. J. Obstet. Gynecol. 157,1082-1089, 1987) describes a method for determining a woman's fertility period based on the measurement of estrogen and PDG in urine with an enzyme-immunoassay method.
  • Brown et. al. (Int. J. Gynecol. Obstet, Suppl. 1, 111-122, 1989) describes the importance of urinary estrogen and pregnanediol measurements in identifying the period of fertility and infertility during the menstrual cycle. They also describe an immunoassay based on reagents coated onto walls of a modified cuvette.
  • J.P. Royston reviews recent progress on the use of statistics in identifying the fertile phase of the human menstrual cycle. Methods using threshold, or Bayesian change-point, and CUSUM (cumulative sum) techniques are discussed.
  • Blackwell and Brown (Steroids, 57: 554-562, 1992) discuss immunochemical assay procedures and suggest to apply time series analysis for the recognition of increase in urinary estrogen as a marker for the beginning of the potential fertile period.
  • U.S. Patent No. 5,118,630 describes a method whereby an increase in pregnanediol glucuronide concentration in urine is compared to a threshold as a means to confirm ovulation.
  • WO 94/04928 describe a method whereby hormones are measured, and along with information about the woman's prior cycles, are used to predict ovulation in the current cycle.
  • Urinary hormone concentrations vary throughout the menstrual cycle. For example, ovulation is generally preceded by an increase in urinary estrogen-type hormones.
  • the level of luteinizing hormone (“LH") increases significantly the day before ovulation occurs. In many tests, the increased LH concentration is indicated by a color change on a dipstick when contacted with a urine sample. Because the test result predicts ovulation before it has happened, it may provide a female with a better chance of conceiving as compared to the traditional methods that indicate that ovulation has already occurred.
  • the present invention provides a method that combines existing hormone assay methods with calculation procedures to optimize the predictive values of daily hormonal changes. In this way a reliable and useful prediction of the fertile period is achieved with the concomitant assurance that the beginning and/or end of the fertile period has been reached so that such declarations are sufficient to provide both fertility enhancement and contraceptive utility.
  • Summary of the Invention provides a method for determining the periodic fertile period in a female, the method including the steps of:
  • the invention also provides a method for determining the first day of the fertile period.
  • the invention further provides a method for determining the final day of the fertile period.
  • the preferred method of the invention predicts both a first and a last day of the fertile period based on daily hormone measurements, most preferably EIG, commencing a fixed number of days usually 1 to 8, preferably 2 to 5, most preferably 5, from the start of menses.
  • the daily hormone measurements continue for a fixed period of time, preferably 10 days, from the start of testing.
  • Figure 1 shows a hard-held meter suitable for use in the method of the invention.
  • Figure 2 shows a disposable self-performing immunochromatography strip suitable for use in the method of the present invention.
  • the present invention relates to an improved method for predicting the day of ovulation by the prospective estimation of a future estrogen hormone level.
  • the invention provides a method for monitoring an optimal period for conception.
  • the present invention provides verification that ovulation has occurred. Therefore, in another aspect, by early prediction and verification of ovulation the invention provides a method for conception prevention.
  • one method of the invention is begun by observing the first day of menses in the menstrual cycle.
  • the level of estrone is measured and the results recorded on a daily basis.
  • Any number of measurement or assay methods known in the art may be used.
  • an important criterion for choosing the measurement or assay method is that the measurement of the hormone marker should be at least precise enough to be semi-quantitative.
  • the result is entered into a calculation means which stores the result and performs calculations, preferably on a daily basis, as will be described in more detail below.
  • the results of the first few days of hormone measurement thus serve as a baseline which is calculated for each female and, therefore reflects cycle variability unique to the user.
  • the beginning of fertile period is declared. From that day, the daily measurement of estrone ceases and a daily measurement of progesterone may begin. Again, progesterone may be measured following techniques known in the art as long as the method is suitable for at least semi-quantitative analysis. These results are also stored and analyzed by a calculation means.
  • the end of the fertility period is declared.
  • a method of the invention comprises the following elements: a) daily measurements of the concentration of one or more fertility hormones in a biological sample; b) a data storage means in which to input the hormone concentration data; c) computational capacity for normalizing the data and fitting a function; d) an evaluation means for extrapolating the fitted function to provide an estimate of the next day's hormone concentration; e) a scoring means for decision making based on the relative slope of the fitted function and the comparison of the expected concentration to the observed concentration on the day of measurement; and f) an output means to indicate the beginning of the fertile period or the end of the fertile period.
  • the result of the strip assay is read by the hand-held meter which also stores the result and performs calculations, as will be described in more detail below.
  • the improved performance of the present invention over the other methods known in the art is due in part to the regime-like mathematical scheme tailored for this particular use which can reliably predict imminent ovulation.
  • the method utilizes a baseline region, a running window, a set of statistical decision making rules, and testing of a fixed duration.
  • a baseline region is calculated and used to study the variation of the observed hormone level in the present menstrual cycle itself as basis for later statistical decision.
  • Each menstrual cycle uses its own baseline without the influence of or reference to previous menstrual cycles or other individuals. This simplifies operation and makes the method independent of cycle-to-cycle variability within the same individual.
  • a running window scheme maximizes the efficiency and improves the sensitivity to significant changes in hormone levels.
  • the statistical rules enhance the validity of decision making and the fixed duration of testing maximizes the efficiency of operation while minimizing expense and labor.
  • the development and optimization of the mathematical scheme will be described in more detail below.
  • An alternate and preferred method of the invention begins by observing the first day of menses in the menstrual cycle. From a pre-selected fixed day, preferably day 5, the level of estrone is assayed and the results recorded on a daily basis.
  • any number of assay methods known in the art may be used, but again, an important criterion for choosing the assay method is that the measurement of the hormone marker should be at least precise enough to be semi-quantitative.
  • the level of estrone in the first few days measurements serve as a baseline unique for the individual female. When an increase in hormone concentration meets the criteria described herein, the beginning of the fertile period is indicated to the user.
  • any number of assay methods known in the art may be utilized in the method of the invention.
  • the assay provide at least a semi-quantitative result (as opposed to a qualitative, i.e., "yes/no” result) be "user-friendly" and uncomplicated. That is, the assay should be sutiable for in-home use by a relatively untrained person. Immunoassays developed for use on dip sticks, membranes, strips, etc. are thus preferred. Most preferred is a disposable, self- performing solid-phase immunoassay strip which, upon use, may be scanned by a reflectance reader as described below. The use of immunochromatography test stips is well known to those skilled in the art.
  • Especially suitable for strips useful in the present invention are those employing colloidal microparticles.
  • the preferred microparticle is described in U.S. Patent 5,252,459 to Tarcha, et al.
  • the '459 patent describes an indicator reagent, method and test kit for the analysis of an analyte in a test sample.
  • an additional and preferred feature of the invention is that the method of the present invention, when the calculation, storage, timing, etc. functions are handled by a microprocessor-based reader, requires no input, or interpretation of results, by the user. Indeed, when such a reader is utilized in the present invention, the information displayed by the reader is a signal or readout indicating that the fertile period has been reached. Thus, there is no quantitative or semi- quantitative result which is displayed for the user. This greatly simplifies the method from the standpoint of the user.
  • the beginning of fertile period is declared. From that day, the daily measurement of estrone estrone continues until a pre-selected fixed day (e.g. day 14) for the end of monitoring. At the end of the monitoring period, the meter processes the stored results of the estrone level using the criteria set by the present invention to predict and declare the end of the fertility period.
  • a pre-selected fixed day e.g. day 14
  • the meter processes the stored results of the estrone level using the criteria set by the present invention to predict and declare the end of the fertility period.
  • the improved performance of the present invention over the other methods known in the art is due in part to the invented regime-like mathematical scheme tailored for this particular use to predict imminent ovulation.
  • the mathematical scheme consists of a baseline region, a running window, a set of statistical decision making rules, and a fixed test duration.
  • a baseline region is used to study the variation of the observed hormone level in the present menstrual cycle itself as basis for later statistical decision.
  • Each menstrual cycle uses its own baseline without the influence of previous menstrual cycles or other individuals. This simplifies operation and avoids complication that no two cycles of the same individual are identical.
  • a running window scheme maximizes the efficiency and improves the sensitivity to detect a significant change in the hormone level.
  • the statsitical rules enhance the validity of decision making.
  • the fixed duration of testing maximizes the efficiency of operation and provide user with friendly operation system.
  • a hand-held meter is described for use in accordance with the invention.
  • Figure 1 illustrates a hand-held meter suitable for use in fertility period monitoring.
  • Figure 2 shows a strip for solid state immunoassay itself.
  • the meter 1 comprises a top casing 104 and a bottom casing 110 with an opening 109 for receiving the carrier 100.
  • a test strip is held in place on carrier 100 by ridge 101 and locating pin 103.
  • gear 102 of carrier 100 engages with the driving gear train of a motor inside the reader.
  • An optical reflectance read head is housed inside the reader depicted as a protrusion 105 of the meter.
  • Assay results as well as user inputs are displayed on a liquid crystal display 108.
  • Two buttons or switches 106 and 107 provide control and user interface to the meter.
  • the solid phase immunoassay strip 2 is supported by a plastic carrier 200 which has a notch 201 complementary to locking pin 103 on carrier 100 to allow reproducible positioning.
  • a reagent pad 202 contains, e.g. a diffusible labeled reagent, and is in contact with nitrocellulose strip 203 which contains an immobilized capture reagent for immuno reaction.
  • the reagent label reacts with steroid in the sample and the complex will be transported along the nitrocellulose strip by capillary action across the capture reagent which immobilizes the label-steroid complex.
  • the intensity of the signal at the capture reagent can then be recorded with a scanning reflectance reader (inside the meter under the read head) 105.
  • the meter is a battery powered device to enhance the portability and convenience of use of the whole system.
  • the hand-held meter is controlled by a microprocessor.
  • Optical elements consist of illumination and photo sensors which function to provide a data string as a reflection reading to a voltage-to-frequency converter for result signals to the processor.
  • a motor provides scanning motion under control of the processor.
  • a real time clock keeps track of timed parameters, e.g., day of testing and day of menstrual cycle.
  • the user interface driver relays the information from and to the processor with the user through a display and control buttons. Batteries and a power supply controller ensures sufficient power that an entire menstrual cycle may be monitored before battery replacement is required.
  • a calibration data bank is also included and functions to convert optical signal to analyte concentration.
  • individual features may be replaced by equivalent on substantially equivalent elements in order to achieve the same objective as outlined above. For example, discrete electronic parts could be replaced with an application specific integrated circuitry (ASIC) and visa versa.
  • ASIC application specific integrated circuitry
  • the term "fitting function” refers to a mathematical expression of the relationship between the day of the menstrual cycle (typically, day 1 through 28) and the hormone concentration that is measured on that day. Although many fitting functions can be applied to the concentration data, three especially useful functions will be described which provide a high degree of certainty for the performance of the present invention.
  • the first fitting function is a simple linear equation and has the advantage of simplicity, fast calculation time, and easy implementation.
  • a 0 and a j are numeric constants determined by the method of least squares.
  • the unit of concentration in this equation is that used in the corresponding assay method.
  • nano-mole per liter is commonly used for assaying estrone 3- glucuronide (E1G) by immunoreaction.
  • E1G estrone 3- glucuronide
  • the linear least square procedure is easily calculated and is well known or can be readily found in any number of reference texts, e.g., "FORTRAN Programs For Engineers and Engineers” , by Alan R. Miller (Sybex Inc., San Francisco (1982).
  • b. Linear Inverse Exponential Function is a non-linear one and has the following formula:
  • a Q , a j and Day are as defined above, and &2 1S another numeric constant determined by the method of least squares.
  • This non-linear fitting function is more complex since the exponential components require more computing power and time to execute. However, with its complex nature, it provides an opportunity to develop the adaptive algorithm to be discussed below.
  • the numeric constants of the function are estimated by the method of least squares to provide a minimum squared difference between the concentration predicted by the fitting function and the actual concentration observed.
  • a2 is the exponential modulus.
  • the use of this function is more complex and usually involves multi-variable optimization iterative search.
  • the Simplex method is one such well known method and is suitable for use in the method of the invention.
  • the Simplex method identifies a basic feasible solution for the constrained multi-variable equations. Then, the method is used to determine whether an optimum value has been reached by subtracting the value calculated from the fitting model for each basis point from the actual analytical value at the point. This difference is squared and the squared difference is used to rank the sets of basis parameters. If an optimum has not been reached, the method provides a way of moving to a new solution that will have a better value of the objective function.
  • four observed hormone concentrations on four consecutive days are set up as four simultaneous equations with a set of starting estimated values of a 0 , a ⁇ , and &2 with 4 slack variables, one for each of the four equations in a tableau. These variables are tested to see whether all the net gains are negative. If it is, then the optimum has been found. If not, the operation of pivoting is carried out using the most marginal net gain variable as the pivot element and removing the variable with the least positive net gain to arrive at a new basic feasible solution with modified variables. The process is repeated until the optimum has been found. The results are a set of values for the fitting function that give least square deviation for the observed hormone concentration. c. Arithmetic Average Function.
  • the third function is a simple arithmetic average calculation. By using average values from a selected range of days as a baseline to set up threshold values for comparison to the observed value of a later day, a mathematical relationship is set up.
  • This function is the most simple to use but not very reliable if used to predict beginning of the fertile cycle because it is more sensitive to data variability than the previously described two functions.
  • a sophisticated function for prediction of the beginning of the fertile period to statistically compensate for the data variation difficulties, such as the linear equation or non-linear equation as described above, a simple method could be used for predicting the end of the fertile period.
  • slope refers to the rate of change in hormone concentration.
  • linear fitting function it is equivalent to the value of a j .
  • non-linear fitting function it is the evaluation of the first derivative of the fitting function.
  • relative slope refers to the value of slope multiplied by 100 then divided by the average values of the observed hormone concentration in the fitting function. In other words, relative slope is the average concentration normalized rate of percentage concentration change. Since function fitting is done on the data in base window, the slope is calculated from data in base window. [Define 'Base Window'] The use of relative slope instead of slope itself reduces sensitivity of decision making to the individual to individual variation.
  • predicted value refers to the threshold value of hormone concentration, based on the fitted function, extending one day beyond the fitting period. For example, if a four day fitting window is used the predicted value of today would the evaluation of the fitted function with the variables least square fitted from the observed hormone concentration of days from 4 days ago to yesterday.
  • threshold value refers to the value of the sum of predicted value and the value of fitting standard deviation multiplied by a chosen multiplier. By comparing the threshold value to the observed hormone concentration, the mathematical processes in the present invention determine whether a change in the trend in the hormone concentration has occurred.
  • the multiplier is similar to a statistical 't test and is selected using similar considerations in that the multiplier "assesses” the confidence level to be given an assessment that an observed change in hormonal concentration warrants an action.
  • the threshold value is the product of "baseline value” with a pre-set multiplier.
  • data variability refers to that property of the concentration measurements that reflect a female's own day to day hormone concentration changes and result in minor deviations from a smooth slope. For example, variability can be caused by the changes in the way the hormone is metabolized in liver, the rate of hormone secretion into the kidney, the volume of liquid secreted by kidney, the concentrating process of urine in the urinary bladder, and variations in the assay method used to quantify the hormone concentration.
  • the t.:- ⁇ n “baseline” refers to the hormone concentrations as measured on several consecutive days that are characterized by relatively low values. Therefore, the baseline values correspond to days where an increase of ovarian activity is unlikely.
  • baseline for E1G represents day 2 to day 5 of each cycle while the baseline for PDG represents the first 4 days of PDG measurement of each cycle.
  • minimal average value refers to the minimal value of a series of four day moving averages.
  • the term "fertile period” refers to that time of the menstrual cycle within which the presence of a viable sperm in the uterus, e.g, via sexual intercourse, would likely lead to conception.
  • score refers to a number that is used to keep a record of an event. For example, the score is set to 0 when the menstrual cycle data analysis starts. When the observed assayed analyte concentration is higher than the threshold value and fulfills the decision rules as explained below, the score would be incremented by 1.
  • decision rules refers to the set of logical relationships that define decision making in the algorithm. This set of rules includes, but is not limited to the following: the difference between the observed concentration compared to the expected concentration; the relative slope compared to the preset threshold of relative slope value; the preset number of trigger points required for action compared to the accumulated trigger points of the cycle up to the day the decision is being made; and the maximal allowable fertile period. For example, a higher observed concentration than expected will give a trigger point if the slope is also positive. A trigger point will be given for each day having slope higher than threshold unless it is one of the baseline days.
  • the beginning or end of the fertile period is declared and the output means will accordingly take action by displaying information and the computational and scoring means are prepared for the next phase, i.e., switching to accept an alternate assay result, e.g., PDG, if the beginning of the fertile period has been declared, or not accepting further assay results until the next cycle starts if the end of fertile period has been declared.
  • an alternate assay result e.g., PDG
  • the assay method can use any of a variety of established biochemical or immunological procedures that can be used in either liquid format or in dry membrane bound solid phase format, such as chemical color reaction assay, enzyme-linked immunoassay (EIA), or radiolabeled immunoassay (RIA).
  • EIA enzyme-linked immunoassay
  • RIA radiolabeled immunoassay
  • 5,120,643 describes a process for immunochromatography with colloidal particles
  • Japanese published application 1109262- A describes an immunoassay of estrogen hormones in body fluid having two or more antibodies to estrogen (conjugate), estradiol (conjugate), and/or estratriol (conjugate) immobilized on a solid phase
  • Japanese patent application 88052705-B described measuring agglutination of latex reagents for diagnosis by measuring an increase in optical absorbance.
  • a solid phase format is preferred. The numerous methods and devices suitable for use in a solid phase format are well known in the art and no special mention need be made in this respect.
  • the hormones or hormone metabolites to be assayed may be obtained from any biological fluid in which such compounds are secreted by the female. Typically, blood and urine are preferred, an early morning sample of urine being the most preferred fluid.
  • the assay can be estrone or other estrogen hormone in blood or the metabolites of the estrone hormones in urine such as estrone 3-glucuronide (E1G).
  • E1G estrone 3-glucuronide
  • U.S. Patent No. 3,544,868 provides a suitable method which can be used to determine steroid hormone glucuronide in urine samples by immunoassay with tracers of glucuronide bound to enzyme.
  • progesterone may be assayed using suitable markers such as serum progesterone or a progesterone metabolite in urine samples such as pregnanediol-glucuronide (PDG).
  • suitable markers such as serum progesterone or a progesterone metabolite in urine samples such as pregnanediol-glucuronide (PDG).
  • PDG pregnanediol-glucuronide
  • any number of methods are known to those skilled in the art, such as gas chromatography, high performance liquid chromatography, enzymatic determination, immuno reactions, etc. and are suitable for use to practice the present invention.
  • the means by which the daily measurement of hormone concentration is accomplished are not important to the present invention. Any suitable means can be used including visual observation, spectrophotometric reading, radioactivity counting, or other electromagnetic readings as appropriate for the chosen assay method.
  • the measurement can be made most typically by a reader which detects and records results of electromagnetic readings. Readers appropriate for the chosen assay methods are well known and the above mentioned references illustrate the wide range of read out formats available.
  • the data storage means, computational capacity, evaluation means, scoring means, and output means can use any number of well known methods for accomplishing these functions. However, it is preferred to incorporate the above means into a single instrument that can function as a unitary device that would require essentially no input from the user other than to input a daily assay to be measured.
  • the beginning of fertile period is predicted using a linear fit function and decision rules having the following parameters: observed hormone concentration greater than 2 times minimal average value for trigger point consideration, 6% relative slope is set as threshold after day 5, threshold value is set by adding 5 times standard deviation to the predicted value, and a score of 4 are required to declare action.
  • this set of parameters is one of the many sets which may be used to assess the performance of the method of invention on a large data base.
  • the particular parameters used here show the application of the method of the invention and the resulting information which is provided by such data analysis.
  • the optimum set of parameters for a large data base can be found by performing a designed experiment of systematic analysis using known ovulation day for reference verification. Further details of the optimization of parameters is found in Example 3 described below.
  • E1G estrogen hormone estrone 3-glucuronide
  • the procedure utilizes the World Health Organization radioimmuno assay (RIA) procedure.
  • the first E1G assay is done on day 2 instead of day 1 so that a clear definition of the start of cycle is given and a simple daily routine is set up to facilitate sample collection and assay performance.
  • the sample is collected from the first early morning passage of urine.
  • Hormone assay is obtained for at least four days with results from each day entered into a microprocessor programmed for linear function calculation. The observed data of the first five days of the cycle are shown in Table 1.
  • the working window is shifted to day 2 to day 6 with a base window of day 2 to day 5.
  • the score reaches the required number for action, namely 4.
  • the beginning of the fertile period for this cycle is declared on day 10.
  • the ovulation day for this particular cycle had been independently established as day 13 by the daily ultrasound observation, i.e., day 13 showed characteristic reduction in follicle diameter as well as other features indicating ovulation such as echo observed in the follicle sac and blurring of follicle borders, etc. Therefore, in this example the method of the invention declares the beginning of fertile period 3 days prior to ovulation.
  • This example describes the method of the invention for predicting the end of the fertile period.
  • This example uses the same menstrual cycle as the one used in Example 1 and measures urinary pregnanediol 3-glucuronide (PDG) assay by the World Health Organization radioimmunoassay method described above.
  • PDG urinary pregnanediol 3-glucuronide
  • This example uses the linear fitting function with the following parameters: 1 times minimal average value, 5 times standard deviation for threshold value, 12% relative slope, and a score of 3 for declaration of end of fertile period.
  • Table 5 shows the observed concentration values and other parameters as analyzed for days 11 through 16 according to the method of the invention.
  • Example 2(a) A four day baseline data is collected for initial relative slope and threshold value calculation similar to the procedures described above for Example 1.
  • day 11 to day 14 provides the four day baseline data of PDG.
  • PDG concentration observed, 11.54 uM is higher than 1 times minimal average value and higher than threshold value of the day.
  • the score is incremented by 1.
  • the score is further incremented by 1 due to a relative slope higher (29.99) than threshold (12) in the base window.
  • the accumulated score of 2 remains less than that required number for action and, therefore, this day is passed without declaring the end of fertile period.
  • observed value is greater than threshold value and score is thus incremented by 1.
  • the resulting incremental score (3) is the number preset as required for action and day 16 is declared as the end of the fertile period for this particular cycle. This is three days after ovulation as determined by ultrasound (Example 1). No additional hormone assays are needed until the beginning of next cycle. At the first day of menses of the next cycle, the procedure for predicting the beginning of fertile period is carried out as described in Example 1.
  • This example uses the third fitting function of arithmetic averaging function.
  • the parameters used are: 5 days after declaration of beginning of fertile period to begin fitting function for ending of fertile period, a value of 2 times the base value as the threshold value for ending of fertile period, and a score of 1 to declare action. In this case the multiplier for standard deviation is zero.
  • the baseline data is obtained from day 11 to day 14.
  • the arithmetic average method calculated the baseline value to 6.5 ⁇ M.
  • the threshold value is then set to 13.0 ⁇ M (2 times base value; as set in the parameters). As shown in the Table 5, day 15 showed 11.54 ⁇ M which is lower than the threshold value of 13.0. Therefore day 15 is passed without action.
  • the observed PDG value is 13.28 ⁇ M, i.e., higher than threshold value.
  • the score is incremented to 1 and the ending of the fertile period is declared because a score of 1 is pre-set for declaration of action. Again, the ending of the fertile period is three days post-ovulation as measured by ultrasound (Example 1).
  • Example 3 Finding the best set of parameters for a large data base
  • the method of the invention can be customized to adjust for earlier detection and declaration of beginning of fertile period (for contraceptive utility) or to adjust for later (i.e., closer to ovulation) detection and declaration of beginning of fertile period (for conception enhancement utility).
  • a large data base with known ovulation day is required.
  • a commonly practiced experimental design can be used for the optimization of parameters. Briefly, it involves many experimental runs with regularly varying combination of parameters. The trends of the effect of varying parameters are analyzed according to the desired relationship to the reference ovulation day. This analysis is then used to predict the best set of parameters for the desired relationship.
  • Tables 6-8 shows the results from a set of data base collected from 170 cycles. The time of ovulation of each menstrual cycle is determined by ultrasound investigation to within 24 hours certainty. Ovulation is declared when the sonographer notes both a reduction in follicle size and a change in follicle appearance by echo pattern and follicle border after rupture.
  • the urinary El G and urinary PDG assays are done following the RIA method of Examples 1 and 2. The parameters tested for this run on this data set are as follows:
  • Table 6 shows the results of predicting the beginning of fertile period of 170 cycles.
  • the first column of the table lists the categories of results relating to ovulation day. For example -9 represents a result that beginning of fertile period is declared 9 days before ovulation occurred.
  • the second column presents the number of cycles that are predicted to have the beginning of fertile period as the corresponding number of days from ovulation in the first column.
  • the third column presents the number in the second column as a percentage fraction of the total number of 170 cycles.
  • the fourth column represents the cumulated fraction of the cycles that have been predicted to have begun fertile period before and on the day shown in the first column before ovulation.
  • the last column represents the remaining fraction of cycles that have not been announced to have entered fertile period.
  • Table 6 shows the results of testing for the ending of fertile period of
  • Example 4 Comparison to known methods. As an additional example, the results of the present invention are compared to those published by J.P. Royston, Statistics in Medicine, 10:221-240 (1991). The Royston reference summarized and assessed the performance of various predictive tests of fertile period based on published data. The data are incorporated into Table 8 and expanded to include data generated by the method of the invention. As is known in the art (see, e.g., pp. 231 of Royston) a commonly accepted criteria for a critical fertility period includes the period of three days pre-ovulation and two days post-ovulation. In Table 8 parameter g is defined as the fraction of cycles that provided a fertile period that overlaps the critical period. Parameter T is an estimate of the dispersion of the distribution of the fertile period around the ideal value of 6. It is calculated by using the following formula:
  • f a stands for the average value of the fertile period and sf stands for the standard deviation of the fertile period.
  • T value which results when using the method of the invention indicates that the present invention is capable of giving a much better defined fertile period in a more reproducible manner.
  • one advantage of the present invention over the prior art methods of predicting fertile period is that a much shorter fertile period is assigned to each cycle.
  • Example 5 Trading optimization for a shorter predicted fertile period.
  • Examples 3 and 4 show a set of optimal parameters which provide good performance and an acceptable predicted fertile period. This example shows that the parameters can be determined by following the experimental design used above but with the goal of a shortened predicted fertile period. This provides an additional advantage of fewer testing days which reduces the number of tests which must be taken and provides a more cost effective and easier to use method.
  • the optimization uses a 169 cycle data base from the same participants as used in Example 3, however, one of the 170 cycle data base was disqualified due to consecutive missed samples half way through the cycle. Ovulation of each menstrual cycle is determined by ultrasound investigation to within 24 hours certainty as before. However, in this case, the first urine sample collected for analysis is done on day 6 of menses. The urinary E1G and urinary PDG assays are done following the RIA method described above. The parameters are set as follows: For beginning of fertile period:
  • Table 9 shows the results of predicting the beginning of fertile period of these 169 cycles. As can be seen in Table 9, a majority of cycles (59%) are declared to have begun fertile period 3 days before actual ovulation (as verified by ultrasound) and only a small fraction of cycles (3.6%) had not been declared to have entered fertile period by the day of ovulation.
  • Table 10 shows the results of testing for the ending of fertile period of the 169 cycles. As can be seen in the cumulated fraction column, less than 4% of cycles are predicted by the method to have ended fertile period on or before the day of actual ovulation (as determined by ultrasound), while a majority of cycles (48% to 67%) are predicted to have ended the fertile period by 4 to 5 days after actual ovulation.
  • Example 5 A comparison of the results from Example 3 (the method of the invention commencing on day 2 of menses) and Example 5 (day 6) is shown in Table 11. As can be seen, the parameters assigned in Example 5 provide certain advantages over those used in Example 3. The predicted length of fertile phase is reduced from 8.4 to 8.1 days with a concomitant reduction in standard deviation of fertile phase from 2 to 1.5. However, this reduction in predicted fertile period results in a reduced index (g) of performance.
  • the effect of this reduction in g value on the predictive value of the method may be less than the numerical value would indicate since it appears mat the reduction is predominately due to a difference of three vs two days pre-ovulation in predicting the start of fertile period.
  • the lower g value may also be offset in part on the presumed use of an early morning urine sample. Therefore, the slightly lower g values which result from commencing the method of the invention on day 6 rather than day 2 are well compensated by the increased benefit of a shorter predicted fertile period and fewer testing days.
  • the beginning of fertile period is predicted using a linear fit function and decision rules having the following parameters: 3% relative slope is set as threshold after day 5, expected value is set by adding 3 times standard deviation to the predicted value, and 3 trigger points are required to declare action.
  • this set of parameters is one of the many sets which may be used to atssess the performance of the method of invention on a large data base.
  • the particular parameters used here show the application of the method of the invention and the resulting information which is provided by such data analysis.
  • the optimum set of parameters for a large data base can be found by performing a designed experiment of systematic analysis using known ovulation day for reference verification. Further details of the optimization of parameters is found in Example 8 described below.
  • the estrogen hormone estrone 3-glucuronide is measured in urine.
  • the procedure utilizes a solid phase immunoassay on nitrocellulose.
  • the first E1G assay is done on day 5 instead of day 1 from the start of menses.
  • the advantage of this most preferred method of the invention is that it reduces the number of assays per cycle required to be performed by the user as well as reducing the possibility of urine samples being contaminated by menstrual flow.
  • the sample is preferably collected from the first early morning passage of urine. Samples and assays are obtained and completed for the first four days (i.e., day 5 to day 8 of the menstrual cycle) with assay results from each day read and stored in the meter.
  • the meter are programmed with the mathematical function of this invention. These first four days assay results serve as data the baseline data as explained above. As explained above, in the preferred method the meter is programed with function of the invention and thus the actual results are not viewed by the user. Accordingly, the internal operation of the calculation process inside the meter is described here in order to more fully explain the method of the invention. The observed data of a first four days results are shown in Table 12.
  • the working window is now shifted to day 5 to day 9 with a.base window of day 5 to day 8.
  • the observed day 9 value (30) is then analyzed according to the method of the invention. In this case the slope is positive (14) but the observed hormone assay value (30) is not higher than the minimal expected value (67.9) and thus there is no trigger point for this feature. However, since the relative slope observed (14) is higher than threshold slope (3) and the day is later than day 8, the trigger point is incremented by 1. However, the trigger point reached (1) is less than set number of 3 and, therefore, day 9 is not the beginning of the fertile period. The process of day 9 is repeated on day 10. The window then shifts to Day 6-10 with a base window of day 6 to day 9. The data observed for day 10 and the results of the method of the invention are shown in the Table 14.
  • the trigger point reaches the required number for action, namely 3.
  • the beginning of the fertile period for this cycle is declared on day 13.
  • the ovulation day for this particular cycle had been independently established as day 17 by the daily ultrasound observation, i.e., day 17 showed characteristic reduction in follicle diameter as well as other features indicating ovulation such as echo observed in the follicle sac and blurring of follicle borders, etc. Therefore, in this example the method of the invention declares the beginning of fertile period 4 days prior to ovulation.
  • Urinary estrone 3 glucuronide is measured by the solid phase immunoassay as described above in Example 6. After the beginning of fertile period is declared in Example 6 day 13, the daily assay of urinary EIG continues until the pre-set day of day 14. On that day calculations commence using the same running window scheme of five days as that used for predicting the beginning of fertile period in Example 6, except the relative slope is calculated from the day of observation itself.
  • default fertile period is 9 days long
  • Table 16 shows the observed concentration values and other parameters as analyzed for day 9 through 14 according to the method of the invention. As shown in Table 16, the relative slope (42.4%) observed on day 13, is greater than the relative slope of day 14 (13.0).
  • a one day reduction infertile period is given for a relative slope greater than threshold (25%) and a fertile period is reduced by one day for reaching maximum on day 13. Therefore, the fertile period for this cycle is 7 days and the end of the fertile period for this cycle is calculated to be day 20.
  • Ovulation day for this menstrual cycle had been determined by the ultrasound reference method on day 17 as mentioned above in Example 6. Thus, this declaration of end of fertile period provides 3 additional subsequent days to ovulation for contraception purposes.
  • Example 8 Determination of Optional Parameters
  • the values assigned to the pre-set parameters e.g., minimal average value, relative slope, threshold slope, multiplier, and the trigger number.
  • the method of the invention can be customized to adjust for earlier detection and declaration of beginning of fertile period (for contraceptive utility) or to adjust for later (i.e., closer to ovulation) detection and declaration of beginning of fertile period (for conception enhancement utility).
  • a commonly practiced experimental design can be used for the optimization of parameters. Briefly, it involves many experimental runs with regularly varying combination of parameters. The trends of the effect of varying parameters are analyzed according to the desired relationship to the reference ovulation day. This analysis is then used to predict the best set of parameters for the desired relationship.
  • Tables 17-19 shows the results from a set of data base collected from 120 cycles.
  • the time of ovulation of each menstrual cycle is determined by ultrasound investigation to within 24 hours certainty. Ovulation is declared when the sonographer notes both a reduction in follicle size and a change in follicle appearance by echo pattern and follicle border after rupture.
  • the urinary EIG assay essentially follows the solid phase immunoassay as described in Examples 6 and 7. The parameters tested for this Example on this data set are as the same as described in Example 6 and 7.
  • Table 17 shows the results of predicting the beginning of fertile period for 120 cycles.
  • the first column of the table lists the results obtained by the method of the invention as compared to actual ovulation day. For example -4 represents a result that the present method declares the beginning of fertile period 4 days before a confined ovulation had occurred.
  • the second column presents the number of cycles that are predicted to have the beginning of fertile period as the corresponding number of days from ovulation in the first column.
  • the third column presents the number in the second column as a percentage fraction of the total number of 120 cycles.
  • the fourth column represents the cumulated fraction of the cycles that have been predicted to have begun fertile period before and on the day shown in the first column before ovulation.
  • the last column represents the remaining fraction of cycles that have not been announced to have entered fertile period. As can be seen in Table 17, a high majority of cycles (66%) are declared to have begun fertile period 3 days before ovulation and only a small fraction (8%) had not been declared to have entered fertile period by 1 day before ovulation. Similarly, Table 18 shows the results of testing for the ending of fertile period of
  • the results of the present invention are compared to those published by J.P. Royston, Statistics in Medicine, 10:221-240 (1991).
  • the Royston reference summarizes and assesses the performance of various predictive tests of fertile period based on published data.
  • the data are incorporated into Table 19 and expanded to include data generated by the method of the invention.
  • a commonly accepted criteria for a critical fertility period includes the period of three days pre-ovulation and two days post-ovulation.
  • parameter g is defined as the fraction of cycles that provided a fertile period that overlaps the critical period.
  • Parameter T is an estimate of the dispersion of the distribution of the fertile period around the ideal value of 6. It is calculated by using the following formula:
  • fa stands for the average value of the fertile period and sf stands for the standard deviation of the fertile period.
  • T value which results when using the method of the invention indicates that the present invention is capable of giving a much better defined fertile period in a more reproducible manner.
  • one advantage of the present invention over the prior art methods of predicting fertile period is that a much shorter fertile period is assigned to each cycle.
  • Examples 8 and 9 show a set of optimal parameters which provide good performance and an acceptable predicted fertile period.
  • the parameters can be determined by following the experimental design used above but with the goal of a shortened predicted fertile period.
  • another set of parameters could be devised to provide an additional advantage of fewer testing days which reduces the number of tests which must be taken and provides a more cost effective and easier to use method.
  • another set of parameters similar to Examples 8, could be devised to provide higher protection with the understood expense in running more assays for a longer period.
  • N/A stands for not applicable.
  • This invention 8.4 2.0 0.48 a 3.2
  • This invention 8.4 2.0 0.61 b 3.2
  • Example 3 8.4 2.0 0.48' 3.2
  • Example 3 8.4 2.0 0.61' 3.2
  • Example 5 8.1 1.5 0.40 ⁇ 2.5
  • Example 5 8.1 1.5 0.48 2.5
  • N/A stands for not applicable.
  • This invention 8.4 2.0 0.65 a 2.7
  • This invention 8.4 2.0 0.68 b 2.7

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Abstract

L'invention se rapporte à un procédé extrêmement fiable consistant à prévoir le début et/ou la fin de la période féconde d'une femme pour chaque cycle menstruel. Ces procédés et ces moyens facilitent l'étude de la variabilité, d'un jour à l'autre, d'un cycle à l'autre, et d'une femme à l'autre, des taux d'hormones de fécondité par l'analyse des mesures de concentrations d'hormones successives au cours des variations hormonales quotidiennes afin de déterminer à quel moment une augmentation réelle et importante de la concentration de l'hormone surveillée a commencé. Par conséquent, la présente invention concerne un procédé qui combine des méthodes de dosage d'hormones existantes avec des procédures de calcul afin d'optimiser les valeurs prédictives des modifications hormonales quotidiennes. On parvient, de cette façon, à obtenir une prévision fiable et utile de la période de fécondité, et on a l'assurance que le début et/ou la fin de la période de fécondité ont été atteints de sorte que, par ces conclusions satisfaisantes, on est à la fois assuré d'une stimulation de la fécondité et convaincu de l'utilité des méthodes contraceptives.
EP95905393A 1993-12-16 1994-12-16 Procedes et moyens de determination de la periode de fecondation chez une femme Withdrawn EP0734531A1 (fr)

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GB9217864D0 (en) 1992-08-21 1992-10-07 Unilever Plc Monitoring method
TR200003830T2 (tr) * 1998-06-22 2002-01-21 Medi-Cult A/S Döllenemez olan yumurtanın varlığının belirlenmesi analizi.
US7427271B2 (en) * 2002-07-01 2008-09-23 Vaclav Kirsner Diagnosis of fertility status by folliculogenesis monitoring in the vagina
JP4150323B2 (ja) * 2003-10-29 2008-09-17 浜松ホトニクス株式会社 免疫クロマト試験片の読取装置、これに用いるカートリッジ及び免疫クロマト試験片の検査システム
US9939385B2 (en) 2011-09-09 2018-04-10 Church & Dwight Co., Inc. Systems, methods, and test kits for analyte variation detection
CN109310403B (zh) * 2016-06-13 2022-09-13 皇家飞利浦有限公司 女性的月经周期期间的面部特性的光学监测
US11061026B2 (en) 2017-02-17 2021-07-13 MFB Fertility, Inc. System of evaluating corpus luteum function by recurrently evaluating progesterone non-serum bodily fluids on multiple days
US11029321B2 (en) 2017-02-17 2021-06-08 MFB Fertility, Inc. Method of evaluating corpus luteum function by recurrently evaluating progesterone non-serum bodily fluids on multiple days
US11131665B1 (en) 2018-08-22 2021-09-28 MFB Fertility, Inc. Method for evaluating urine of a subject to estimate the fertile window
EP4017375A4 (fr) * 2019-08-19 2023-12-06 MFB Fertility, Inc. Systèmes et procédés de test de cycle menstruel

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IE54109B1 (en) * 1982-02-10 1989-06-21 Boots Celltech Diagnostics Assay
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WO1993007578A1 (fr) * 1991-10-01 1993-04-15 Emil Josef Biggel Appareil de prediction du cycle menstruel

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