Methods and systems for assessment of clinical infertility

• US 10,438,686 B2
• Filed: 08/19/2016
• Issued: 10/08/2019
• Est. Priority Date: 07/01/2008
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Yao, Mylene W. M., Wong, Wing H.
• Primary Examiner(s): Kuhlman, Catherine B
• Application Number:
  US15/242,215
• Publication Number:
  US 20160357917A1
• Time in Patent Office: 1,145 Days
• CPC Class Codes: A61B 17/425 for reproduction or fertilisation specially adapted for use with animals A61D19/00
• CPC Class Codes: C12Q 1/6809 Methods for determination or identification of nucleic acids involving differential detection
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
• CPC Class Codes: G16B 25/10 Gene or protein expression profiling; Expression-ratio estimation or normalisation
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/30 Unsupervised data analysis
• CPC Class Codes: G16B 5/00 ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
• CPC Class Codes: G16B 5/20 Probabilistic models
• CPC Class Codes: G16H 10/60 for patient-specific data, e.g. for electronic patient records
• CPC Class Codes: G16H 40/20 for the management or administration of healthcare resources or facilities, e.g. managing hospital staff or surgery rooms
• CPC Class Codes: G16H 50/30 for calculating health indices; for individual health risk assessment
• CPC Class Codes: G16H 70/20 relating to practices or guidelines
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Methods and computer-based systems for facilitating assessment of clinical infertility are provided. The methods and systems can be implemented to, for example, facilitate assessment of a subject for an in vitro fertilization treatment cycle, including determining probability of a live birth event. The methods and systems can be implemented to, for example, facilitate a determination of success implantation of embryos, selection of an optimal number of embryos to transfer, and determination of success in subsequent in vitro fertilization treatment cycles following an unsuccessful treatment cycle.

Claims

1. A system comprising:

(a) a computing environment;

(b) an input device in communication with the computing environment, wherein the input device comprises a platform for entry of a fertility profile for a female subject and for entry of data sets, the data sets comprising,

(i) a first data set comprising fertility profiles of a group of female individuals, wherein successful and unsuccessful IVF treatments from the fertility profiles are identified within the data set,

(ii) a second data set comprising clinical variables known to be associated with or influence a female individual'"'"'s probability of having a live birth event, and

(iii) a third data set comprising variables related to in vitro fertilization (IVF) treatment protocols;

(c) a non-transitory computer readable storage medium in communication with the computing environment comprising at least one algorithm that,

(i) analyzes the data sets of (b) to identify variables from the data sets that are predictive of a probability of a live birth event in a female individual undergoing an IVF treatment,

generates a prediction model for a likelihood of a female individual having a live birth event from an IVF treatment based upon the identified variables of (c)(i), validates the prediction model by testing the prediction model on at least one independent data set comprising fertility profiles of a group of female individuals, wherein the fertility profiles of the group of female individuals have variables that are correlated to the variables of (c)(i) that were found to be predictive of the probability of the live birth and applies the validated prediction model to the at least one independent data set to generate prognostic stratification of the independent data set, wherein the prognostic stratification is represented by percentile assignments representing a likelihood of the female individuals of the at least one independent data set to experience a live birth event from an IVF treatment, and

(iii) applies the validated prediction model and prognostic stratification of (c)(ii) to the fertility profile of the female subject of (b) to obtain the female subject'"'"'s predictive probability of having a live birth event from an IVF treatment and the percentile assignment of the female subject'"'"'s probability of having a live birth event from an IVF treatment relative to the female individuals of the at least one independent data set;

(d) an output device in communication with the computing environment for providing results generated by the at least one prediction model for the female subject, wherein the results are deliverable to a user of the system as a fertility management protocol for the female subject based upon the predicted probability and percentile assignment of (c)(iii).

2. The system of claim 1, wherein a successful IVF treatment comprises data on a live birth outcome.

3. The system of claim 1, wherein the variables known to be associated with or influence a female individual'"'"'s probability of having a live birth event are selected from the group consisting of age, previous infertility history, number of previous pregnancies, number of previous term deliveries, number of spontaneous miscarriages, number of previous unsuccessful IVF treatments, body mass index, day 3 follicle stimulating hormone (FSH) level or other estimates of ovarian reserve, contraceptive use, number of motile sperm before wash, number of motile sperm after wash, number of total motile sperm after wash, number of total motile sperm before wash, sperm collection, sperm from donor, age of sperm donor or male partner, methods and origin of sperm collection, endometrial thickness, ultrasound monitoring results, clinical diagnosis of infertility, and combinations thereof.

4. The system of claim 3, wherein the variable related to clinical diagnosis of infertility is selected from the group consisting of diminished ovarian reserve, endometriosis, hydrosalpinx, polycystic ovarian disease, tubal disease, tubal ligation, male infertility, male infertility causes, unexplained female infertility, uterine fibroids, other causes of female infertility, and combinations thereof.

5. The system of claim 1, wherein the variables related to IVF treatment protocols are selected from the group consisting of oral contraceptive use, downregulation by gonadotropin-releasing hormone agonists (GnRHa), dosage of GnRHa, number of times GnRHa injected per day, use of GnRH antagonist, clinical criteria for starting GnRH antagonists, type of gonadotropins administered, total dosage of gonadotropins, use of human chorionic gonadotropin, dosage of human chorionic gonadotropin, clinical criteria for administering human chorionic gonadotropin, time interval between human chorionic gonadotropin administration and oocyte retrieval, downregulation initiated in menstrual cycle luteal phase, frequency of ultrasound monitoring, type of progesterone supplementation, performance of intracytoplasmic sperm injection (ICSI), assisted hatching, medications used, number of days of stimulation, and combinations thereof.

6. The system of claim 1, wherein the input device is configured to receive a fourth data set (iv) comprising oocyte and/or embryo parameters for a group of female individuals.

7. The system of claim 6, wherein the oocyte and/or embryo parameters are cohort-specific oocyte and embryo parameters.

8. The system of claim 6, wherein the oocyte and/or embryo parameters are selected from the group consisting of number of oocytes, number or percent of normal and mature oocytes, number or percent of normally fertilized eggs, number or percent of unfertilized eggs, number or percent of abnormally fertilized eggs, time for appearance of 2 pronuclei morula and blastocyst to be observed after insemination, time for appearance of 2 cell morula and blastocyst to be observed after insemination, time for appearance of 4 cell morula and blastocyst to be observed after insemination, time for appearance of 8 cell morula and blastocyst to be observed after insemination, total number of embryos on day 3 of embryo culture, total number of embryos on day 5 of embryo culture, assisted hatching, average grade of embryos, average number of cells per embryo, blastocyst development rate, compaction on day 3 of embryo culture, rate of cleavage arrest, number or percent of embryos arrested at the 4-cell stage, day of embryo transfer, number or percentage of 8-cell embryos, number or percentage of 8-cell embryos transferred, number or percentage of blastocysts, number or percentage of cryopreserved embryos, number or percentage of cryopreserved oocytes, season of procedure, year of procedure, sufficient quality for cryopreservation, and pre-implantation genetic testing positive for genetic disease or aneuploidy.

9. The system of claim 6, wherein the oocyte and/or embryo parameters comprise data from one or more single cell embryos.

10. The system of claim 6, wherein the oocyte and/or embryo parameters comprise data from one or more embryos with at least two cells.

11. The system of claim 6, wherein the oocyte and/or embryo parameters comprise data from one or more embryos at a morula or blastocyst stage.

12. The system of claim 6 wherein the oocyte and embryo parameters comprise data from one or more oocytes or embryos in arrested development.

13. The system of claim 6, wherein the oocyte and embryo parameters comprise data from one or more cryopreserved embryos.

14. The system of claim 6, wherein the oocyte and/or embryo parameters comprise data for normalized gene expression levels for one or more infertility indicator genes.

15. The system of claim 14, wherein the data for the normalized gene expression levels for the one or more infertility indicator genes are measured from samples selected from the group consisting of one or more embryos, one or more oocytes, a fertilized egg, dissociated cells, one or more dissociated embryos, one or more dissociated oocytes, and combinations thereof.

16. The system of claim 15, wherein the one or more embryos are single cell embryos.

17. The system of claim 15, wherein the one or more embryos are embryos with at least two cells.

18. The system of claim 15, wherein the one or more embryos are embryos at a morula or blastocyst stage.

19. The system of claim 15, wherein the one or more embryos are cryopreserved embryo.

20. The system of claim 15, wherein the one or more dissociated embryos are dissociated blastomeres.

21. The system of claim 14, wherein the data for the normalized gene expression levels for the one or more infertility indicator genes is output from a procedure selected from the group consisting of a gene chip, a BioMark®

Dynamic Array, RT-PCR, gene sequencing, and combinations thereof.

22. The system of claim 14, wherein the one or more infertility indicator genes are selected from the group consisting of ADM, β

-ACTIN, BCLAF1, BMPR1A, BRF2, BTAF1, BTBD14A, CBX4, CCNA1, CCNA2, CDC2, CDH1, CDH2, CDT1, CENPE, CITED2, CPSF4, CPSF6, CRB3, CSE11, CS1L, CTSB, DIDOI, DNMT3A, DNMT3B, DPPA5, E112, ECSIT, EIF2C5, EIF2S1, EIF3B, EIF3C, EIF3E, EIF3G, EIF3H, EIF3S, EIF3S10, EIF4E, EIF4E2, EIF4G1, EIF5B, EIF6, ETF1, ETV1, EZH2, FGF4, FGFRI, FGFRL1, GATA4, GATA6, GAPDH, GENS, GJA1, GTF3C1, GTF3C2, GTF3C4, GTF3C5, H3F3A, HAT1, HBEGF, HIPK1, HIPK3, HNRPA1, HNRPAB, HRNPK, HNRPM, I117RD, IGF2R, IMP1, INTS4, INTS7, JMJD2A, JMY, KDM3A, KDM3B, KDM5B, KDM5C, KFF9, KIF11, KIF22, KITLG, KLF9, KRTI6, LIN26, M113, MAPK1, MCM3, MCM5, MED8, MEDI4, METT12, MKRN1, MRIF1, MTA2, NANOG, NES, NRF1, OCT4, ORC41, PA2G4, PAPOLA, PARD3, PELP1, PIWIL2, PKNOX1, POLR2H, POLR3A, POLR3E, POLR3K, POU5F1, PPM1A, PPM1G, PPP2CB, PRKAG1, PRKCA, PRKCD, PRPF4, PRPF38B, PURB, RARS, RBM3, RBM4, RMB5, REST1, RFC2, RFC3, RSC8, SALL4, SESN1, SFRS15, SGPP1, SIRT1, SMARCA4, SMARCC1, SNUPN, SOX2, TAF9, TCEB3, TEFL5, TSTT1, UBTF, UGDH, and YY1.

23. The system of claim 14, wherein the one or more infertility indicator genes are selected from a molecular fingerprint of normal human embryos.

24. The system of claim 23, wherein the normal human embryos are selected from single-cell samples, multi-cell samples, or pooled embryo samples.

25. The system of claim 23, wherein the molecular fingerprint comprises data obtained from analysis of genes that are differentially expressed between normal and abnormal embryo samples.

26. The system of claim 25, wherein the normal and abnormal embryo samples are human or animal embryo samples.

27. The method of claim 25, wherein abnormal embryo status is based upon characteristics selected from the group consisting of lack of responsiveness to IVF treatment, arrested embryo development, failure to produce a pregnancy, biochemical pregnancy, spontaneous abortion, and combinations thereof.

28. The method of claim 25, wherein the analysis of genes that are differentially expressed between normal and abnormal embryo samples comprises removing one gene from a normal embryo through a gene targeting procedure.

29. The method of claim 28, wherein the gene targeting procedure is selected from the group consisting of homologous recombination, transgenesis, injection of anti-sense morpholino oligonucleotides, and combinations thereof.

30. The system of claim 1, wherein the input device is configured to receive a fifth data set (v) comprising information relating to oocyte culture, embryo culture, and fertilization.

31. The system of claim 30, wherein the information relating to oocyte culture, embryo culture, and fertilization are selected from the group consisting of culture group, number of oocytes per culture group, number of embryos per culture group, volume of culture media droplet used, brand of culture media, manufacturer of culture media, lot of culture media, whether ICSI is performed, time interval between oocyte retrieval and oocyte insemination, temperature of culture environment, gas composition of culture environment, brand and manufacturer of equipment used in culture environment, brand and manufacturer of equipment used for embryo procedures, and combinations thereof.

32. The system of claim 31, wherein the information relating to oocyte culture, embryo culture, and fertilization is gas composition of the culture environment, wherein the gas composition of the culture environment is selected from the group consisting of percentage of O₂, percentage of CO₂, percentage of N₂, and combinations thereof.

33. The system of claim 31, wherein the information relating to oocyte culture, embryo culture, and fertilization is brand and manufacturer of equipment used for embryo procedures, wherein the embryo procedures are selected from the group consisting of assisted hatching and embryo transfer.

34. The system of claim 1, wherein the computing environment (a) comprises at least one local computer local to the user and at least one remote computer at a site remote to the user, wherein the at least one local computer and the at least one remote computer are in communication through a network.

35. The system of claim 34, wherein the communication between the at least one local computer and the at least one remote computer is selected from the group consisting of an intranet network, an internet network, a wired connection, a wireless connection, a cellular phone connection protocol, code derived multiple access, and a global system for mobile communication.

36. The system of claim 1, wherein the input device (b) is selected from the group consisting of a personal computing device, a mobile device, a portable computer, a mainframe, a minicomputer, and a Smartphone device.

37. The system of claim 1, wherein the computer readable storage medium (c) is provided on a computer remote to the input device.

38. The system of claim 1, wherein the system transmits part or all of the input from the user entered into the input device (b) and/or the results of from the output device (d) electronically or telephonically to the user.

39. The system of claim 1, wherein the system electronically transmits part or all of the input from the user entered into the input device (b) and/or the results from the output device (d) directly to an electronic medical record for the female subject.

40. The system of claim 1, wherein the algorithm of the computer readable storage medium (c) provides relative weighting of the variables.

41. The system of claim 1, wherein the algorithm of the computer readable storage medium (c) uses a decision rule, a classification tree, a multiple additive regression tree, gradient boosting, logistic regression, nonparametric techniques, or combinations thereof.

42. The system of claim 1, wherein the algorithm of the computer readable storage medium (c) detects differences in a distribution of feature values.