Metabolic phenotyping

• US 8,577,617 B2
• Filed: 09/19/2008
• Issued: 11/05/2013
• Est. Priority Date: 06/14/2002
• Status: Expired due to Fees

• Current Assignee: Jeremy Kirk Nicholson, Jeremy Ramsey Everett, John Christopher Lindon, Thomas Andrew Clayton
• Original Assignee: Jeremy Kirk Nicholson, Jeremy Ramsey Everett, John Christopher Lindon, Thomas Andrew Clayton
• Inventors: Clayton, Thomas Andrew, Everett, Jeremy Ramsey, Lindon, John Christopher, Nicholson, Jeremy Kirk
• Primary Examiner(s): Clow, Lori A
• Application Number:
  US12/233,996
• Publication Number:
  US 20090192721A1
• Time in Patent Office: 1,873 Days
• Field of Search: None
• US Class Current: 702/19
• CPC Class Codes: G01N 33/5038 involving detection of metabolites per se

Abstract

A method of generating models with which to characterize selected aspects of the metabolic phenotype of subjects without dosing a test substance to those subjects or with which to predict, without dosing, the post-dose responses of subjects where those responses are dependent on metabolic phenotype, the method comprising: obtaining pre-dose data relating to a plurality of subjects before dosing with a dosing substance; obtaining post-dose data relating to the plurality of subjects after dosing with the dosing substance; and correlating inter-subject variation in the pre-dose data with inter-subject variation in the post-dose data, and generating a pre-to-post-dose predictive model on the basis of the observed correlation. The models may be used to determine selected aspects of the metabolic phenotype of a subject or to predict, without dosing, the post-dose responses of subjects. This is achieved by analysing data relating to the un-dosed subject in relation to a model describing the correlation of pre-dose and post-dose data relating to a plurality of subjects when dosed with a particular substance which challenges the biochemical transformation or pathway of interest; and generating, according to the predetermined criteria of the model, a numerical measure or classification describing the metabolic phenotype of the un-dosed subject.

Claims

1. A model system, wherein the model predicts, without dosing, the post-dose response of an individual where the response is dependent on the individual'"'"'s metabolic phenotype, the model system comprising:

a) pre-dose data of a plurality of subjects or samples thereof before dosing with a dosing substance;

b) post-dose data of the plurality of subjects or samples thereof after dosing with the dosing substance; and

c) a processor that identifies and correlates inter-subject variation in the pre-dose data with inter-subject variation in the post-dose data using a pattern recognition (PR) technique, wherein the inter-subject variation in the post-dose data corresponds to different responses of the subjects to the dosed substance, thereby producing a pre-to-post-dose predictive model,

wherein the processor applies the pre-to-post-dose predictive model to the individual'"'"'s pre-dose data and classifies the individual'"'"'s post-dose response, without dosing of the individual;

wherein the pre- and/or post-dose data comprise chemical composition data and/or physical parameter data of samples and/or subjects;

wherein the pre-to-post-dose predictive model consists of one or more mathematical equations defining the relationship between pre-dose and post-dose data.

2. The model system according to claim 1, wherein the pre- and/or post-dose data are obtained from samples which are biofluids such as urine, blood, blood plasma, blood serum, saliva, sweat, tears, breath or breath condensate.

3. The model system according to claim 2, wherein the pre- and/or post-dose samples or subjects are treated prior to analysis so as to enhance data recovery or to improve sample stability.

4. The model system according to claim 1 wherein the pre- and/or post-dose data are derived from or are compositional data acquired using nuclear magnetic resonance (NMR) spectroscopy and/or any other chemical analysis techniques such as mass spectroscopy (MS), infrared (IR) spectroscopy, gas chromatography (GC) and high performance liquid chromatography (HPLC) or by using any integrated combination of such techniques.

5. The model system according to claim 4 wherein the pre- and/or post-dose data are physical data or data derived therefrom.

6. The model system according to claim 1 wherein, the model system comprises the post-dose data of a plurality of dosing substances.

7. The model system according to claim 6 wherein the pre-dose data set is extended, prior to pattern recognition, by taking ratios and/or other combinations of existing variables.

8. The model system according to claim 7 wherein, for a group of subjects dosed with any particular substance, the pattern recognition method is used to identify patterns in the variable metabolism of, or the variable reactions to, the dosing substance.

9. The model system according to claim 1 wherein, for a group of subjects dosed with any particular substance, a supervised pattern recognition method is used to identify variation in the pre-dose data that correlates with the variation of interest in the post-dose data.

10. The model system according to claim 1 wherein the model identifies biomarkers or combinations of biomarkers which are used to predict responses to dosing.