Methods for determining menstrual cycle time point

A method for determining a statistical model for determining menstrual cycle time point, the method comprising:

• a) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• b) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• c) a gene expression profile can be determined based on a test endometrial sample;
• d) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• and
• d) the menstrual cycle time point of the test endometrial sample can be determined based on the scores.

A method for determining menstrual cycle time point from an endometrial sample, the method comprising:

• a) determining a gene expression profile from a test endometrial sample;
• and
• b) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene;
• and
• c) determining menstrual cycle time point of the test endometrial sample based on the scores,
• wherein:
• d) gene expression profiles can be determined from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• e) a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene can be determined from the gene expression profiles,
• wherein the statistical model can be determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines can be used to obtain an expected gene expression value for a given time point in the menstrual cycle.

A method for diagnosing an endometrial disorder, condition or disease in a subject, the method comprising:

• a) determining a gene expression profile from a test endometrial sample of a subject suspected of having an endometrial disorder, condition or disease;
• and
• b) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene,
• wherein the gene expression profile is normalised for menstrual cycle time point by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• (c) a gene expression profile can be determined from a test endometrial sample;
• (d) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• the menstrual cycle time point of the test endometrial sample can be determined based on the scores;
• wherein known endometrial samples and test endometrial samples from the subject suspected of having an endometrial disorder, condition or disease that are determined to belong to the same menstrual cycle time point are used for diagnosing the endometrial disorder, condition or disease;
• and
• wherein the comparison between the gene expression profile of the test sample and statistical models for each respective gene is determinative of the diagnosis of the endometrial disorder, condition or disease in the subject.

A method for treating an endometrial disorder, condition or disease in a subject, the method comprising:

• a) determining a gene expression profile from a test endometrial sample of a subject suspected of having an endometrial disorder, condition or disease;
• and
• b) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene,
• wherein the gene expression profile is normalised for menstrual cycle time point by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• c) a gene expression profile can be determined from a test endometrial sample;
• d) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• e) the menstrual cycle time point of the test endometrial sample can be determined based on the scores;
• and
• wherein the method uses known endometrial samples and test endometrial samples from the subject that are determined to belong to the same menstrual cycle time point,
• wherein the comparison between the gene expression profile of the test sample and statistical models for each respective gene is determinative of the diagnosis of the endometrial disorder, condition or disease in the subject;
• and
• f) administering a therapeutically effective amount of a treatment to the subject based on the diagnosis of the endometrial disorder, disease or condition in the subject, thereby treating an endometrial disorder, disease or condition in the subject.

Use of a therapy for treating an endometrial disorder, disease or condition in a subject, the therapy comprising:

• a) determining a gene expression profile from a test endometrial sample of a subject suspected of having an endometrial disorder, condition or disease;
• and
• b) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene,
• wherein the gene expression profile is normalised for menstrual cycle time point by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determinized by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• c) a gene expression profile can be determined from a test endometrial sample;
• d) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• e) the menstrual cycle time point of the test endometrial sample can be determined based on the scores;
• and
• wherein the method uses known endometrial samples and test endometrial samples from the subject that are determined to belong to the same menstrual cycle time point,
• wherein the comparison between the gene expression profile of the test sample and statistical models for each respective gene is determinative of the diagnosis of the endometrial disorder, condition or disease in the subject;
• and
• f) administering a therapeutically effective amount of a treatment to the subject based on the diagnosis of the endometrial disorder, disease or condition in the subject.

A method for determining uterine receptivity for embryo implantation (e.g., in vitro fertilisation, IVF) in a subject, the method comprising:

• a) determining a gene expression profile from a test endometrial sample of a subject requiring embryo implantation;
• and
• b) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene of a respective menstrual cycle time point,
• wherein the statistical models are determined by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines are used to obtain an expected gene expression value for a given time point in the menstrual cycle,
• wherein the gene expression profiles are used to determine a statistical model that defines a relationship between the gene expression profile and the determinization of uterine receptivity for embryo implantation for each respective gene and wherein the comparison is determinative of uterine receptivity for embryo implantation in the subject.

A method for assigning an age to a subject based on menstrual cycle time point, the method comprising:

• a) determining a gene expression profile from a test endometrial sample;
• and
• b) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene,
• wherein the comparison is determinative of the age the subject;
• and
• wherein the gene expression profile is normalised for menstrual cycle time point by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the spline are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• c) a gene expression profile can be determined from a test endometrial sample;
• d) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• e) the menstrual cycle time point of the test endometrial sample can be determined based on the scores;
• and
• wherein the method uses known endometrial samples and test endometrial samples from the subject that are determined to belong to the same menstrual cycle time point.

A screening method for identifying one or more biomarkers of an endometrial disorder, disease or condition, the method comprising:

• a) determining gene expression profiles from endometrial samples of subjects that are suspected of having, or have been diagnosed with an endometrial disorder, disease or condition;
• and
• b) determining from the gene expression profiles a statistical model that defines a relationship between the gene expression profile and the endometrial disorder, disease or condition,
• wherein the gene expression profile is normalised for menstrual cycle time point by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the spline are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• c) a gene expression profile can be determined from a test endometrial sample;
• d) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• e) the menstrual cycle time point of the test endometrial sample can be determined based on the scores;
• and
• wherein the method uses known endometrial samples and test endometrial samples from the subject that are determined to belong to the same menstrual cycle time point,
• wherein a score that indicates differential expression compared to a corresponding gene from a sample of a subject not having an endometrial disorder, disease or condition is identified as a biomarker of the endometrial disorder, disease or condition.

A method for assessing the responsiveness of a subject to a treatment for an endometrial disorder, disease or condition, the method comprising:

• a) obtaining or having obtained a test endometrial sample from a subject having been treated for an endometrial disorder, disease or condition,
• b) determining a gene expression profile from the test endometrial sample;
• and
• c) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene of a subject of a respective treatment,
• wherein the comparison is determinative of the responsiveness of an endometrium sample to the therapy;
• and
• wherein the gene expression profile is normalised for menstrual cycle time point by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• d) a gene expression profile can be determined from a test endometrial sample;
• e) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• f) the menstrual cycle time point of the test endometrial sample can be determined based on the scores;
• and
• wherein the method uses known endometrial samples and test endometrial samples from the subject that are determined to belong to the same menstrual cycle time point.

A method for assessing the effect of a therapeutic treatment on endometrium gene expression profile, the method comprising:

• a) obtaining or having obtained an endometrial test sample from a subject treated for a disorder, disease or condition;
• b) determining a gene expression profile from a test endometrial sample of a subject having received a therapeutic treatment;
• and
• c) determining scores for the test sample based on a comparison between the gene expression profile of the test sample and statistical models for each respective gene of a sample of a subject of a respective treatment,
• wherein the comparison is determinative of a change to an endometrium gene expression profile;
• and
• wherein the gene expression profile is normalised for menstrual cycle time point by:
• i) determining gene expression profiles from endometrial samples of known menstrual cycle time points across the entire menstrual cycle, wherein each gene expression profile is determined by measuring gene expression of a plurality of genes of the endometrial sample;
• and
• ii) determining, from the gene expression profiles, a statistical model that defines a relationship between the gene expression profile and the menstrual cycle time point for each respective gene, wherein the statistical model is determined by fitting regression splines to gene expression data associated with each respective gene, whereby the splines are used to obtain an expected gene expression value for a given time point in the menstrual cycle;
• wherein:
• d) a gene expression profile can be determined from a test endometrial sample;
• e) scores can be determined for the test sample based on a comparison between the gene expression profile of the test sample and the statistical models for each respective gene;
• f) the menstrual cycle time point of the test endometrial sample can be determined based on the scores;
• and
• wherein the method uses known endometrial samples and test endometrial samples from the subject that are determined to belong to the same menstrual cycle time point.