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Title:
METHODS FOR PROVIDING A PERSONALIZED THERAPEUTIC TREATMENT REGIME FOR ADDICTIONS
Document Type and Number:
WIPO Patent Application WO/2023/220213
Kind Code:
A1
Abstract:
The present invention provides a method for identifying a patient with an increased risk for an addiction comprising the steps of: providing a patient; obtaining a biological sample from the patient, wherein the biological sample a buccal sample, a saliva sample, and a urine sample; analyzing the biological sample for one or more biomarkers; recording the biomarker data from one or more biomarkers, wherein the one or more biomarkers include one or more neurotransmitters, one or more hormones, one or more genes; comparing the biomarker data to a biomarker standard to produce a bioinformatic analysis; evaluating the bioinformatic analysis to determine a personalized therapeutic regime; and providing the personalized therapeutic regime to the patient.

Inventors:
HIGGINS EVELYN (US)
HALL JACQUELINE (US)
Application Number:
PCT/US2023/021782
Publication Date:
November 16, 2023
Filing Date:
May 10, 2023
Export Citation:
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Assignee:
HIGGINS EVELYN (US)
HALL JACQUELINE (US)
International Classes:
G01N33/483; G16B20/20; G16B25/10; G01N33/487; G16H20/10
Foreign References:
JP2009528063A2009-08-06
CN104053450A2014-09-17
RU2622082C22017-06-09
US20120283114A12012-11-08
Attorney, Agent or Firm:
SINGLETON, Chainey, P. (US)
Download PDF:
Claims:
What is claimed is:

1. A method for identifying a patient with an increased risk for an addiction comprising the steps of: providing a patient; obtaining a biological sample from the patient, wherein the biological sample a buccal sample, a saliva sample, and a urine sample; analyzing the biological sample for one or more biomarkers; recording the biomarker data from one or more biomarkers, wherein the one or more biomarkers include one or more neurotransmitters, one or more hormones, one or more genes; comparing the biomarker data to a biomarker standard to produce a biomformatic analysis; evaluating the bioinformatic analysis to determine a personalized therapeutic regime; and providing the personalized therapeutic regime to the patient.

2. The method of claim 1 wherein the one or more neurotransmitters, one or more hormones or both comprise Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine ratio, Glutamate, Gammaaminobutyrate, Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA.

3. The method of claim 1 wherein the one or more genes are selected from C3, CD 14, IL2, IL4, IL5, IL6, IL 13, STAT4, TNF, TRAF1, IL23R, IL2RA, SOCS1, CTLA4, IDO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1, HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8. UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO-A, MAO-B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V.

4. The method of claim 1 wherein the biomarker data comprises neurotransmitters levels, hormones levels.

5. The method of claim 1 wherein the biomarker data comprises between 60-125 pg/g Serotonin, 125-250 pg/g Dopamine, 22-50 pg/g Norepinephrine, 1.6-8.3 pg/g Epinephrine, <13 Norepinephrine/Epinephrine Ratio, 12.0-45.0 pmol/g Glutamate, 12.0-5.6 pmol/g Gamma-aminobutyrate, 450-2200 pmol/g Glycine, 14- 44 pg/g Histamine, 32-84 nmol/g Phenethylamine, and 30-225 mg/dL Creatine.

6. The method of claim 1 wherein the biomarker data comprises the DHEA Saliva range between 200-400 pg/ml.

7. The method of claim 1 wherein the biomarker data comprises a Cortisol salivia range between 2-4AM is <1.0 ng/ml, a Cortisol salivia range at 7AM between 7.0-10.0 ng/ml, a Cortisol salivia range at 12PM between

3.0-6.0 ng/ml, a Cortisol salivia range at 5PM between 2.0-4.0 ng/ml, and a Cortisol salivia range at 10PM <1.5 ng/ml.

8. The method of claim 1 wherein the biomarker data comprises gene qualsEy, gene mutations. gene abnormalities or a combination thereof.

9. A method for identifying a patient with an increased risk for an addiction comprising the steps of: providing a patient; obtaining a biological sample from the patient, wherein the biological sample a buccal sample, a saliva sample, and a urine sample; analyzing die biological sample to

(a) determine a neurotransmitter profile comprising the concentrations of one or more neurotransmitters,

(b) to determine a hormone profile comprising the concentrations of one or more hormones, and

(c) to determine a gene profile comprising data relating to a gene quality , a gene mutation arid a gene abnormality for one or more genes; determining a patient biodeficiency profile by comparing

(a) the neurotransmiter profile to a neurotransmiter profile standard,

(b) the hormone profile to a hormone profile standard, and

(c) the gene profile to a gene profile standard; analyzing the patient biodeficiency profile to determine an optimized personalized therapeutic regime; and providing the optimized personalized therapeutic regime to the patient.

10. The method of claim 9, wherein the one or more neurotransmitters, one or more hormones or both comprise Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine ratio, Glutamate, Gamma-aminobutyrate, Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA.

11. The method of claim 9, wherein the one or more genes arc selected from C3, CD14, IL2, IL4, IL5, IL6, IL 13, STAT4, TNF, TRAF1, IL23R, IL2RA, SOCS1, CTLA4, IDO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1, HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO-A, MAO-B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V.

12. The method of claim 9 wherein the biomarker data comprises between 60-125 pg/g Serotonin, 125-250 pg/g Dopamine, 22-50 pg/g Norepinephrine, 1.6-8.3 pg/g Epinephrine, <13 Norepinephrine/Epinephrine Ratio, 12.0-45.0 pmol/g Glutamate, 12.0-5.6 pmol/g Gamma-aminobutyrate, 450-2200 pmol/g Glycine, 14- 44 pg/g Histamine, 32-84 nmol/g Phenethylamine, and 30-225 mg/dL Creatine.

13. The method of claim 9 wherein the biomarker data comprises the DHEA Saliva range between 200-400 pg/ml.

14. The method of claim 9 wherein the biomarker data comprises a Cortisol salivia range between 2-4AM is <1.0 ng/ml, a Cortisol salivia range at 7AM between 7.0-10.0 ng/ml, a Cortisol salivia range at 12PM between 3.0-6.0 ng/ml, a Cortisol salivia range at 5PM between 2.0-4.0 ng/ml, and a Cortisol salivia range at 10PM <1.5 ng/ml.

15. The method of claim 1, wherein biomarker data comprises genomic information, proteomic information, biochemical information or metabolomic information obtained from analysis of a sample.

16. The method of claim 1, wherein the analysis comprises any of or a combination of the following: genotyping; haplotyping; analysis of the patient's RNA; analysis of the patient's DNA; analysis of the patient's proteome; and analysis of the patient's metabolome.

17. The method of claim 1, further comprising the step of obtaining feedback information to determine an updated personalized therapeutic regime according to the effects of the personalized therapeutic regime on the patient and further comprising administering the updated personalized therapeutic regime to the patient.

Description:
METHODS FOR PROVIDING A PERSONALIZED THERAPEUTIC TREATMENT REGIME FOR ADDITCTIONS

Technical Field of the Invention

The present invention relates in general to the field of addiction diagnosis, prognosis, and treatment to provide an optimized personalized therapeutic treatment regime to the patient.

Background Art

Without limiting the scope of the invention, its background is described in connection with addiction diagnosis, prognosis, and treatment of disorders at using an optimized personalized therapeutic regime. The present invention also relates to diagnostics prognostics and treatment at the genetic level for numerous diseases and medical conditions.

Methods of genetic analysis by looking at one or a few genes are known in the art. In particular “genotyping” or “haplotyping”, together with genomic and proteomic analysis have lead to the identification of certain genes, alleles, haplotypes, SNPs or other genetic indicia or loci that are connected or related in some way to certain diseases or conditions; however, their use is quite limited and fails to provide a reliable mechanism for evaluating treatments. As such, the administration of certain drug therapies is not necessarily guaranteed successful given the inherent genetic differences even between closely related individuals.

For example, United States Patent Number 8,080,371, entitled “Markers for addiction,” discloses correlations between polymorphisms and addiction are provided. Methods of diagnosing, prognosing, and treating addiction are provided. S stems and kits for diagnosis, prognosis and treatment of addiction are provided. Methods of identifying addiction modulators are also described.

United States Patent Application Publication Number US20110251243, entitled “Method and Kit for Assessing a Patient's Genetic Information, Lifestyle and Environment Conditions, and Providing a Tailored Therapeutic Regime,” discloses a method of determining a personalized therapeutic regime, comprising: receiving genetic information relating to a patient; determining genetic criteria relevant to a personalized therapeutic regime for the patient using the genetic information; receiving personal information relating to the patient; determining personal criteria relevant to the personalized therapeutic regime using the personal information; and combining the genetic criteria and the personal criteria to determine the personalized therapeutic regime for the patient.

United States Patent Application Publication Number US20110189161, entitled “Nutrigenomics methods and compositions,” discloses a proprietary compositions and systems to modulate genetic and metabolomic contributing factors affecting disease diagnosis, stratification, and prognosis, as well as the metabolism, efficacy and/or toxicity associated with specific vitamins, minerals, herbal supplements, homeopathic ingredients, and other ingredients for the purposes of customizing a subject's nutritional supplement formulation to optimize specific health outcomes.

Disclosure of the Invention

The present invention provides a method for identifying a patient with an increased risk for an addiction comprising the steps of: providing a patient; obtaining a biological sample from the patient, wherein the biological sample a buccal sample, a saliva sample, and a urine sample; analyzing the biological sample for one or more biomarkers; recording the biomarker data from one or more biomarkers, wherein the one or more biomarkers include one or more neurotransmitters, one or more hormones, one or more genes; comparing the biomarker data to a biomarker standard to produce a bioinformatic analysis; evaluating the bioinformatic analysis to determine a personalized therapeutic regime; and providing the personalized therapeutic regime to the patient. The method wherein the one or more neurotransmitters, one or more hormones or both comprise Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine ratio. Glutamate, Gammaaminobutyrate, Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA. The method wherein the one or more genes are selected from C3, CD 14, 1L2, 1L4, 1L5, IL6, 1L13, STAT4, TNF, TRAF1, 1L23R, 1L2RA, SOCS1, CTLA4, 1DO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1, HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO-A, MAO-B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V. The method wherein the biomarker data comprises neurotransmitters levels, hormones levels. The method wherein the biomarker data comprises between 60-125 ug/g Serotonin, 125-250 pg/g Dopamine, 22-50 jxg/g Norepinephrine, 1.6-8.3 pg/g Epinephrine, <13 Norcpincphrinc/Epincphrinc Ratio, 12.0-45.0 pmol/g Glutamate, 12.0-5.6 pmol/g Gamma-aminobutyrate, 450-2200 pmol/g Glycine, 14-44 pg/g Histamine, 32-84 nmol/g Phenethylamine, and 30-225 mg/dL Creatine. The method wherein the biomarker data comprises die DHEA Saliva range between 200-400 pg/ml. The method wherein the biomarker data comprises a Cortisol salivia range between 2-4AM is <1.0 ng/ml, a Cortisol salivia range at 7AM between 7.0-10.0 ng/ml, a Cortisol salivia range at 12PM between 3.0-6.0 ng/ml, a Cortisol salivia range at 5PM between 2.0-4.0 ng/ml, and a Cortisol salivia range at 10PM <1.5 ng/ml. The method wherein the biomarker data comprises gene quality, gene mutations, gene abnormalities or a combination thereof.

The present invention provides a computer based system for identifying a patient with an increased risk for an addiction comprising the steps of: providing a patient; obtaining a biological sample from the patient, wherein the biological sample a buccal sample, a saliva sample, and a urine sample; analyzing the biological sample for one or more biomarkers; recording the biomarker data from one or more biomarkers, wherein the one or more biomarkers include one or more neurotransmitters, one or more hormones, one or more genes; comparing the biomarker data to a biomarker standard to produce a bioinformatic analysis; evaluating the bioinformatic analysis to determine a personalized therapeutic regime; and providing the personalized therapeutic regime to the patient.

The present invention provides a method for identifying a patient with an increased risk for an addiction comprising the steps of: providing a patient; obtaining a biological sample from the patient, wherein the biological sample a buccal sample, a saliva sample, and a urine sample; analyzing the biological sample to (a) determine a neurotransmitter profile comprising the concentrations of one or more neurotransmitters, (b) to determine a hormone profile comprising the concentrations of one or more hormones, and (c) to determine a gene profile comprising data relating to a gene quality, a gene mutation and a gene abnormality for one or more genes; determining a patient biodeficiency profile by comparing (a) the neurotransmitter profile to a neurotransmitter profile standard, (b) the hormone profile to a hormone profile standard, and (c) the gene profile to a gene profile standard; analyzing the patient biodeficiency profile to determine an optimized personalized therapeutic regime; and providing the optimized personalized therapeutic regime to the patient.

The method wherein the one or more neurotransmitters, one or more hormones or both comprise Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine ratio, Glutamate, Gammaaminobutyrate, Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA. The method wherein the one or more genes are selected from C3, CD 14, IL2, IL4, IL5, IL6, IL13, STAT4, TNF, TRAF1, IL23R, IL2RA, SOCS1, CTLA4, IDO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1 , HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO-A, MAO-B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V. The method wherein the biomarker data comprises between 60-125 pg/g Serotonin, 125-250 pg/g Dopamine, 22-50 pg/g Norepinephrine, 1.6-8.3 pg/g Epinephrine, <13 Norepinephrine/Epinephrine Ratio, 12.0-45.0 pmol/g Glutamate, 12.0-5.6 pmoVg Gamma-aminobutyrate, 450-2200 pmol/g Glycine, 14- 44 pg/g Histamine, 32-84 nmol/g Phenethylamine, and 30-225 mg/dL Creatine. The method wherein the biomarkcr data comprises the DHEA Saliva range between 200-400 pg/ml. The method wherein the biomarker data comprises a Cortisol salivia range between 2-4 AM is <1.0 ng/ml, a Cortisol salivia range at 7AM between 7.0-10.0 ng/ml, a Cortisol salivia range at 12PM between 3.0-6.0 ng/ml, a Cortisol salivia range at 5PM between 2.0-4.0 ng/ml, and a Cortisol salivia range at 10PM <1.5 ng/ml. The method wherein biomarker data comprises genomic information, proteomic information, biochemical information or metabolomic information obtained from analysis of a sample. The method wherein the analysis comprises any of or a combination of the following: genotyping; haplotyping: analysis of the patient's RNA; analysis of the patient's DNA; analysis of the patient's proteome; and analysis of the patient's metabolome. The method further comprising the step of obtaining feedback information to determine an updated personalized therapeutic regime according to the effects of the personalized therapeutic regime on the patient and further comprising administering the updated personalized therapeutic regime to the patient.

The present invention provides computer system that implements a method for identifying a patient with an increased risk for an addiction comprising the steps of: providing a patient; obtaining a biological sample from the patient, wherein the biological sample a buccal sample, a saliva sample, and a urine sample; analyzing the biological sample to (a) determine a neurotransmitter profile comprising the concentrations of one or more neurotransmitters, (b) to determine a hormone profile comprising the concentrations of one or more hormones, and (c) to determine a gene profile comprising data relating to a gene quality, a gene mutation and a gene abnormality for one or more genes; determining a patient biodeficiency profile by comparing (a) the neurotransmitter profile to a neurotransmitter profile standard, (b) the hormone profile to a hormone profile standard, and (c) the gene profile to a gene profile standard; analyzing the patient biodeficiency profile to determine an optimized personalized therapeutic regime; and providing the optimized personalized therapeutic regime to the patient.

Description of the Drawings

The present invention as described herein does not include any figures.

Description of the Invention

While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.

To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

The present invention employs a method of using science and technology informing genetic measurement of addiction to quantify the physiology of addiction and provide treatment informed by evidence-based testing. More specifically, the present invention provides a process to identify, isolate, and measure the biological components of addiction. Guided by data driven research and outcomes, the present invention uses numerous biomarkers to review the specific genetic single nucleotide polymorphisms, neurotransmitters, and hormones involved in the physiological triangle of addiction. For example, in one embodiment, the present invention selects 85 biomarkers to review the specific genetic single nucleotide polymorphisms, neurotransmitters, and hormones (STIGMA panel) involved in the physiological triangle of addiction. However, the specific number of biomarkers used may vary depending on the specific application. For example, in some applications it may all be necessary to examine a more limited number of biomarkers, e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80. In other applications it may be necessary to examine more than 85 biomarkers, e g., 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140,1 45, 150. As stated above, the specific number of biomarkers can be between 1 and 85 and even up to 150 or more. The specific examples given above increase in increments of 5. However, this is not to be limiting in that the skilled artisan readily know that the actual number of biomarkers may be any integer between 1 and 150 and it is unnecessary and redundant to list out every integer between 1 and 150. Filling an enormous gap in addiction treatment, the present invention provide evidence-based testing of biomarkers present in individuals battling addiction, and create a hyper- precise treatment based on the Biomarker Evaluation Report informed by objective data.

The present invention employs a method of using science and technology informing genetic measurement of addiction to quantify the physiology of addiction and provide treatment informed by evidence-based testing. The first step is to gather the individual information. This information we gathered in numerous ways, the most common being an intake questionnaire. The specific information and intake data collected may depend on the specific analysis. For example, common intake data includes aberrant behavior, history of substance abuse or misuse, family medical history, family history of addiction, dual diagnosis, symptom expression, pharmaceutical use, and lifestyle.

The present invention also includes a selection of specific genes, neurotransmitters and hormones that will be used in the evaluation. For example a nonlimiting list of neurotransmitters and hormones include Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine ratio, Glutamate, Gammaaminobutyrate, Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA. Similarly, a nonlimiting list of genes include genes that code for C3, CD14, IL2, IL4, IL5, IL6, IL13, STAT4, TNF, TRAF1, IL23R, IL2RA, SOCS1, CTLA4, IDO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1, HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO-A, MAO-B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V.

The present invention provides for specimen sample to be taken from a patient. The sample may be in the form of anything known to the skilled artisan that will allow the collection of the sample. For example, the sample may be collected from buccal, saliva, and urine. It is also possible that separate samples from separate sources may be taken from a single individual. Once a sample is collected, it is sent to be analyzed at a laboratory . One such example of a laboratory is a CLIA laboratory. The Clinical Laboratory Improvement Amendments (CLIA) regulate laboratory testing and require clinical laboratories to be certified by the Center for Medicare and Medicaid Services (CMS) before they can accept human samples for diagnostic testing. Pharmacogenomic test is included in the analysis of the sample. Once the sample has been analyzed the laboratory returns reports and results those results are interpreted into a Biomarker Evaluation Report. The present invention provides through the analysis of the biomarker evaluation report a prescription of nutraceuticals and pharmaceuticals with individual specific dosing is created and shared with patient to support the appropriate biochemical pathways at the appropriate level. For example, based on the report an individual is provided with a list of pharmaceuticals that are considered safe, to be used with caution, and to be avoided based on their unique physiology. The present invention provides a list of prescribed treatments that may be beneficial to the patient. This allows the patient to be prescribed that specific treatment protocol and the results monitored. For example, a patient is prescribed a specific treatment protocol which he takes for a period of 6 months and during this time a symptom tracker is used together empirical evidence of the improvements resulting from the specific treatment protocol. This allows the effectiveness of the treatment protocol to be empirically evaluated and modifications made as necessary. The patient may be retested by taking another sample at any time during this treatment period. For example, a common reevaluation timeframe is 6 months as it allows sufficient time to utilize a symptom tracker results that have been gathered. When the specific treatment protocol is reevaluated by taking a sample and running the same biochemical pathway analysis the effectiveness of the treatment can be evaluated through evidence-based data.

Example 1. In this study, 1 control participant (Control) and 1 independent participant (Patient) were evaluated. The control participant was a 52 year old Caucasian male self-reporting alcoholism and problem gambling. The independent participant was a 61 year old Caucasian female self-reporting alcoholism and opiate abuse.

A sample was taken from the control participant in the form of buccal, saliva, and mine samples to be used as a control variable sample. The genes analyzed included: C3, CD14, IL2, IL4, IL5, IL6, IL13, STAT4, TNF, TRAF1, IL23R, IL2RA, SOCS1, CTLA4, IDO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1, HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO-A, MAO- B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V. The neurotransmitters and hormones analyzed included: Serotonin, Dopamine, Norepinephrine, Epinephrine,

Norepinephrine/Epinephrine ratio, Glutamate, Gamma-aminobutyrate, Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA.

The analysis of the control participants genes indicated no clinical abnormality: FOLR1, DFR, MTHFR, MTR, GIF, TCN2, GC or DBP, NDUFS7, NDUFS8, UQCRC2, UQCRC2, IL2, IL4, IL13, TNF, IL23R, CTLA4, DRD2, ATG5, ATG16Li, ATG16L1, AHCY, GSTM1, AOC1, HNMT, HNMT, NOS2, HLADRB1, GAD1, MAO-A, HTR2, TPH2, MTHFR1298, AHOY, GSTM1, S0D1, SOD3, NAT2, and MTF. The analysis of the control participants genes with a heterozygous result included: MTHFS, MTHFD1, MTHFRC677T, SLC19A1, MRTTA664A, TCN1, VDRTaq, NDUFS3, COX5A, COX6C, ATP5C1, CoQ2, C3, CD14, IL6, STAT4, TRAF1, IDO1, ATG12, CTH, GSTP1I105V, HLADQA21, HLADQA2, HLADRB2, COMTV158M, GAD1, MTHFR677, CTH, GSTP1I105V, SOD2, and GPX3. The analysis of the control participants genes with a homozygous result included: FOLR2, MTRRA66G, IL5, ILF2RA, SOCS1, FUT2, MAO-B, SLC6A4, DBH, GSR, and GSTM3.

The sample showed the control participant reference ranges for Serotonin, Gamma-aminobutyrate, Dopamine, Norepinephrine, Epinephrine, Glutamate, Glycine, Histamine, Phenethylamine, Norepinephrine/Epinephrine Ratio, and Creatine were 42-105 pg/g, 1.4-5 pmol/g, 90-220 pg/g, 12-50 pg/g, 0.9-9.2 pg/g, 8-24 pmol/g, 280-2800 pmol/g, 10-48 pg/g, 16-146 nmol/g, and <10 respectively. The control participant had a DHEA reference range is 137-336 pg/mL, Cortisol 10:30AM 14-25 nmol/L, Cortisol 12PM 5 0-10 nmol/L, Cortisol 5PM 2.0-5.0 nmol/L, and Cortisol 10PM 1.0-4.0 nmol/L. His results were as follows: Serotonin 105 pg/g, Gamma-aminobutyrate 3.5 pmol/g, Dopamine 176 pg/g, Norepinephrine 21.8 pg/g, Epinephrine 3.2 pg/g, Glutamate 19 pmol/g, Glycine 296 pmol/g, Histamine 34 pg/g, Phenethylamine 95 nmol/g, Norepinephrine/Epinephrine Ratio 6.8, and Creatine 56 mg/dL. His DHEA reference range is 137-336 pg/mL, Cortisol 10:30AM 14-25 nmol/L, Cortisol 12PM 5.0-10 nmol/L, Cortisol 5PM 2.0-5.0 nmol/L, and Cortisol 10PM 1.0-4.0 nmol/L. His DHEA result is 130 pg/mL, Cortisol 10:30AM 17 nmol/L, Cortisol 12PM 4.7 nmol/L, Cortisol 5PM 1.7 nmol/L, and Cortisol 10PM 1.0 nmol/L. The control participant returned a pharmacogenomic test results which did not impact his pharmaceutical use as he does not take any medications. Based on this data and information and the analysis of that data and information the control participant was prescribed a specific protocol of nutraceuticals and pharmaceuticals.

The control participant did not change his lifestyle, drinking habits, eating habits, sleeping habits, and did not follow the recommended protocol of nutraceuticals and pharmaceuticals based on his panel results. The control participant retested on 6 months later and his results were as follows: genes with no clinical abnormality: FOLR1, DFR, MTHFR, MTR, GIF, TCN2, GC or DBP, NDUFS7, NDUFS8, UQCRC2, UQCRC2, IL2, IL4, IL13, TNF, IL23R, CTLA4, DRD2, ATG5, ATG16Li, ATG16L1, AHCY, GSTM1, AOC1, HNMT, HNMT, NOS2, HLADRB1, GAD1, MAO-A, HTR2, TPH2, MTHFR1298, AHCY, GSTM1, SOD1, SOD3, NAT2, and MTF. Genes with a heterozygous result included: MTHFS, MTHFD1, MTHFRC677T, SLC19A1, MRTTA664A, TCN1, VDRTaq, NDUFS3, COX5A, COX6C, ATP5C1, CoQ2, C3, CD14, IL6, STAT4, TRAF1, IDO1, ATG12, CTH, GSTP1I105V, HLADQA21, HLADQA2, HLADRB2, COMTV158M, GAD1, MTHFR677, CTH, GSTP1I105V, SOD2, and GPX3. Genes with a homozygous result included: FOLR2, MTRRA66G, IL5, ILF2RA, SOCS1, FUT2, MAO-B, SLC6A4, DBH, GSR, and GSTM3. The Control’s reference ranges for Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine Ratio, Glutamate, Gamma-aminobutyrate, Glycine, histamine, Phenethylamine, and Creatine were 50-98 pg/g, 110-200 pg/g, 18-42 pg/g, 1.3-7.3 pg/g, <13, 9.0-40.0 pmol/g, 1.6-3.5, 350- 1500 pmol/g, 12-30 pg/g, 26-70 nmol/g, and 35-240 mg/dL respectively. The control participant’s results, were as follows: Serotonin 70.7 pg/g, Dopamine 166 pg/g, Norepinephrine 18.7 pg/g, Epinephrine 2.1 pg/g, Norepinephrine/Epinephrine Ratio 8.9, Glutamate 16 pmol/g, Gamma-aminobutyrate 3.6 pmol/g, Glycine 364 pmol/g, Histamine 26 pg/g, Phenethylamine 59 nmol/g, and Creatine 91.2 mg/dL. His DHEA reference range is 137-336 pg/mL, Cortisol 10:30AM 14-25 nmol/L, Cortisol 12PM 5.0-10 nmol/L, Cortisol 5PM 2.0-5.0 nmol/L, and Cortisol 10PM 1.0-4.0 nmol/L. His DHEA result is 75 pg/mL, Cortisol 10:30AM 14 nmol/L, Cortisol 12PM 3.2 nmol/L, Cortisol 5PM 1.1 nmol/L, and Cortisol 10PM 0.99 nmol/L.

In the 6 months following the initial testing, the control participant retested utilizing the same 85 STIGMA Panel biomarkers. In summation, of the 16 neurotransmitters and hormones measured, measured 14 suboptimal with clinical correlations supporting the control participant’s self-reported addictive tendencies. Epinephrine, norepinephrine, Norepinephrine / Epinephrine ratio, Gamma-aminobutyrate, Glycine, Glutamine, Histamine, Phenethylamine, and Creatine levels all declined without biochemical pathway support and continuation of lifestyle habits. The urine samples measuring the control participant’s nemotransmitters provide an assessment of the body’s ability to catabolize neurotransmitters which impact the central and peripheral nervous systems. The levels revealed during STIGMA panel validate the fatigue, insomnia, cravings, addiction, body pain, diminished drive, and focus issues reported by the control participant. Specifically, the low range epinephrine and norepinephrine are associated with mood change, fatigue, depression, lack of focus, decreased ability to stay on task, and diminished drive. The control participant’s elevated Gamma-aminobutyrate exacerbates his inability to concentrate, contribute to memory loss, low mood, fatigue, and decreased endurance.

Of the 69 Genetic Single -Nucleotide Polymorphisms, 29 had either heterozygous or homozygous results. The following were the genes and gene categories were tested and analyzed: Detoxification enzymes are responsible for clearing environmental chemicals and metabolites from our body. Accumulation of these chemicals and by-products can damage intracellular biochemical functions. Alterations in these systems can have a significant negative effect on the nervous system and immune systems functions. These polymorphisms can result in decreased "quality of life" and even decreased "life-span". AHCY Adenosylhomocysteinase (AHCY) is an enzyme that breaks down S-adenosylhomocysteine (SAH) to homocysteine and adenosine. Polymorphisms in this gene will lead to lower levels of homocysteine and glutathione. CTH Glutathione production is dependent on the function of the enzyme cystathionine gammalyase (CTH). CTH converts cystathionine to cysteine. Individuals with mutations in the CTH gene are predicted to have decreased glutathione-mediated detoxification. GPX3 The protein encoded by this gene belongs to the glutathione peroxidase family which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione. This reduction functions to protect cells against oxidative damage. The GPX3 isoz me is secreted and is abundantly found in plasma, as well as intracellularly. Down regulation of expression of this gene by promoter hypermethylation has been observed in a wide spectrum of human disease states. GSR The glutathione reductase (GSR) gene encodes a protein involved in metabolizing glutathione. Mutations in this gene are associated with impaired cellular redox homeostasis. GSTM1 Glutathione S-transferase Ml (GSTM1) is an important enzyme in the body's detoxification pathway. GSTM1 conjugates glutathione to molecules (drugs, environmental toxins, carcinogens etc.) bound for excretion. GSTM1 is mainly responsible for binding toxins in joints and for binding carcinogens. GSTM3 Glutathione S- transferase mu 3 is an enzyme that detoxifies drugs, environmental toxins, and carcinogens by conjugating toxins to glutathione and subsequent excretion by the kidneys. Mutations in GSTM3 are associated with decreased clearance of toxins, anesthetics and drugs from the nervous system. GSTP1 Glutathione S- transferases (GSTs) are a family of enzymes that play an important role in detoxification. The glutathione S- transferase pi gene (GSTP1) functions in chemical clearance and anti-inflammatory properties. High concentration of GST-p are found in the skin, lungs, sinuses, bladder and the intestinal tract. Polymorphisms of this enzyme allow for increased inflammatory activity in these areas that include eczema, asthma, chronic sinusitis, IBS, "leaky" gut and interstitial cystitis. NAT2 N-Acetyl Transferase 2 (NAT2) is a liver enzyme that functions to both activate and deactivate drugs and carcinogens. Polymorphisms in this gene are divided into rapid, intermediate, and slow acetylator phenoty pes. The slow polymorphism phenotype of NAT2 are also associated with higher incidences of cancer and drug toxicity. SOD1 The protein encoded by this gene binds copper and zinc ions and is one of two isozymes responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic protein, acting as a homodimer to convert naturally - occurring, but harmful superoxide radicals to molecular oxygen and hydrogen peroxide. The other isozyme is a mitochondrial protein. Mutations in this gene have been implicated as causes of familial amyotrophic lateral sclerosis. Rare transcript variants have been reported for this gene SOD2 Mitochondrial Superoxide Dismutase 2 (SOD2) is a member of the iron/manganese mitochondrial superoxide dismutase family. This protein transforms toxic superoxide, a byproduct of the mitochondrial electron transport chain, into hydrogen peroxide and oxygen. This function allows SOD2 to clear mitochondrial reactive oxygen species (ROS) and, as a result, confer protection against mitochondrial damage and cell death. SOD3 Cytomplasmic Superoxide Dismutase 3 (SOD3) is a member of the superoxide dismutase family. This protein transforms toxic superoxide, a byproduct of certain cellular functions, into hydrogen peroxide and oxygen. This function allows SOD2 to clear and confer protection against mitochondrial damage and cell death. DEVELOPMENTAL The SNPs in this category have been identified as potential areas of weakness in the recovery of developmental disorders. ATG12 Autophagy-related 12 protein is part of the core autophagy machinery inside the cell. Autophagy, a form of cellular "recycling" is necessary for many cell functions. ATG12 is specifically involved in turning off the innate immune response. Mutations in the ATG12 gene are predicted to lead to increased activity of the innate immune response, and overall inflammation. ESSENTIAL VITAMINS The polymorphisms in this panel will identify any potential weakness of absorption, conversion or delivery or your essential vitamins. COQ2 CoQ2 (Para-hydroxybenzoate — polyprenylfransferase, mitochondrial) codes for an enzyme that functions in the final steps in the biosynthesis of CoQlO (ubiquinone). This enzyme, which is part of the coenzyme Q10 pathway, catalyzes the prenylation of parahydroxybenzoate with an all-trans polyprenyl group. Mutations in this gene cause coenzyme Q10 deficiency. Polymorphisms in this gene can lead to severe fatigue, muscle weakness, exercise intolerance and general mitochondrial weakness. GC or DBP GC aka DBP (Vit. D Binding Protein) gene codes for Vit. D binding protein. This protein belongs to the albumin family and is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It is manufactured in the hepatic parenchymal cells. DBP is capable of binding to all forms of Vit D including ergocalciferol (vitamin D2) and cholecaldiferol (vitamin D3), the 25 -hydroxylated forms (calcifediol) and the active hormonal product, 1,25- dihydroxyvitamin D (calcitriol). The major proportion of vitamin D in blood is bound to this protein. It transports vitamin D metabolites between skin, liver and kidney, and then on to the various target tissues. It binds to vitamin D and its plasma metabolites and transports them to target tissues. Polymorphisms in this gene decrease the affinity of the protein to Vit. D which reduces the response rate to Vit. D therapy. Patients with these polymorphisms require high doses of Vit D supplementation. J. Hall - NUG2022-01023 35 March 4, 2022 INFLAMMATORY This Enzyme category has significant effects on the inflammatory state of a person's body. Polymorphisms in these specific enzymes will significantly increase the levels of inflammation in the body. By supplementing these enzyme deficiencies, the patient will effectively reduce inflammatory damage to the body. AOC1 The SNP rsl0156191 encodes a weaker form of the histamine degradation enzyme Amine Oxidase, Copper Containing 1 (AOC1). This mutation, Thrl6Met, is predicted to produce an enzyme with less catalytic activity and associated higher levels of pro-inflammatory amines like histamine and putrescine. ATG16L1 rsl0210302 The ATG16L1 gene encodes a protein that is a vital component of a protein complex necessary for the cellular phenomena known as autophagy. Autophagy is the process of degrading and cleaning of inert debris of the cell. Weakness in autophagy leads to abnormal accumulation of cellular “garbage” that will eventually affect the cellular function and lead to autophagy -related disease states in including many neurological and immunological diseases, DM Type 2 and fatty liver disease. ATG5 Autophagy -related 5 protein (ATG5) is an important intracellular mediator of the autophagy response. ATG5 is involved in a wide range of "quality control" features inside the cell: autophagy vesicle formation, innate immune system signaling, consumption of damaged mitochondria, and apoptosis. Mutations in the ATG5 gene are associated with numerous neurological, immunological and endocrine syndromes. C3 Essential for the immune response, C3 is a protein involved in initiation of the complement system. C3 polymorphisms are associated with susceptibility to asthma and other inflammatory disorders. CD14 The CD14 protein is a macrophage cell surface receptor that binds bacterial cell wall components. As one of the initiators of the innate immune response, fully functional CD14 is necessary for normal response to potential pathogens. Mutations in the CD 14 gene are associated with susceptibility to asthma and other allergen-mediated inflammatory processes. CTLA4 Cytotoxic T-lymphocyte Associated protein 4 (CTLA4) is an important inhibitor of T-cell activity: CTLA4 is part of the signaling cascade that turns off overactive T cells. Mutations in the gene that encodes CTLA4 arc associated with a host of diseases characterized by a heightened immune state. DRD2 Dopamine receptor D2 is an important component of the neuroinflammation process. Activation of DRD2 signaling is thought to decrease TNFalpha release from inflammatory mast cells. Polymorphisms associated with decreased DRD2 signaling activity are predicted to lead to pro -inflammatory phenotypes. FUT2 Fucosyltransferase 2 (FUT2) is responsible for producing specific sugar groups that are secreted by the intestinal cells into the bowel to attract "good bacteria" . Polymorphisms in this gene produce "poor secreter" status. Lack of these sugars allows for gut dysbiosis and a higher risk of inflammatory bowel disease. HLA- DQA1 Major histocompatibility complex, DQ alpha 1 (HLA-DQA1) is a human gene responsible for a cell surface receptor essential to the function of the immune system. Patients with a polymorphism in this gene are at higher risk for auto-immune based inflammatory disease including Celiac disease, Crohn's, Ulcerative Colitis, and gluten sensitivity. HLA-DQA2 Major histocompatibility complex, DQ alpha 2 (HLA-DQA2) is a human gene responsible for a cell surface receptor essential to the function of the immune system. Patients with a polymorphism in this gene are at higher risk for auto-immune based inflammatory disease including Celiac disease, Crohn's, Ulcerative Colitis, and gluten sensitivity. HLA-DRB1 Human leukocyte antigen DRB1 (HLA-DRB1) is an important mediator of the adaptive immune system. HLA-DRB1 protein "presents" antigens from invading pathogens to other cells in the immune system. Mutations in this gene are associated with higher risk of auto-immunity and other chronic inflammatory diseases. HLA-DRB2 Human leukocyte antigen DRB2 (HLA-DRB2) is a cell surface receptor involved in mediating the adaptive immune response. Mutations in HLA-DRB2 are associated with susceptibility to chronic inflammation and decreased ability to recover from toxic mold exposure. HMNT rsl2995000 The HNMT gene encodes the histamine degradative enzyme, histamine N-methyltransferase. HNMT, in contrast to AOC1, requires the methyl donor S- adenosylmethionine and a complete methylation pathway for normal function. Polymorphisms in HNMT gene expression or protein-coding are predicted to prolong the pro-inflammatory effects of histamine signaling. HNMT Thrl05Ile The HNMT gene encodes the histamine degradative enzyme, histamine N- methyltransferase. HNMT, in contrast to AOC1, requires the methyl donor S-adenosylmethionine and a complete methylation pathway for normal function. Polymorphisms in HNMT gene expression or protein coding are predicted to prolong the pro-inflammatory effects of histamine signaling. IL13 IL13 (Interleukin 13) is a member of the interleukin family of chemical messengers of the immune system. Polymorphisms in this gene are associated with changes in IL 13 gene expression and increase the risk of more severe inflammatory responses to allergens. IL2 IL2 (Interleukin 2) codes for a secreted cytokine that is important for the proliferation of T and B lymphocytes. The receptor of this cytokine by interleukin 4 (IL4). Overall, the polymorphism of IL4 produces a robust inflammatory response to allergic stimuli which can be associated with severe allergic symptoms, immune cancer risk and bowel inflammation. IL23R A/A and A/G genotypes at rs 11209026, a polymorphism in the Interleukin 23 Receptor gene (IL23R), provide a protective effects against Crohn's disease. IL2RA Polymorphisms in a non-protein coding region of the Interleukin 2 Receptor subtype A (IL2RA) are associated with increased risk of multiple sclerosis in some populations. IL4 IL4 (Interleukin 4) codes for a plcio tropic cytokine produced by activated T cells. The interleukin 4 receptor also binds to IL 13, which may contribute to many overlapping functions of this cytokine and IL 13. The STAT system, a signal transducer and activator of transcription, has been shown to play a central role in mediating the immune regulatory signal of this cytokine. Overall, the polymorphism of IL4 produces a robust inflammatory response to allergic stimuli which can be associated with severe asthma, allergies, chronic sinusitis, as well as, migraines and bowel inflammation. IL5 The protein product of the Interleukin 5 gene (IL5) is important for normal development of B lymphocytes and eosinophils (a pro -inflammatory white blood cell). Inactivating mutations in the IL5 gene are associated with susceptibility to certain viral infections and increased aggression of inflammatory response. These polymorphisms are also associated with increased aggression of allergies, asthma and eosinophilia. IL6 Interleukin 6, IL6, is an important pro-inflammatory cytokine. Polymorphisms in this gene leads to a more aggressive inflammatory response. Patients with IL-6 mutations require assistance with inflammatory control. NOS2 Nitric Oxide Synthanse 2 (NOS2) is responsible for producing nitric oxide, a biologic mediator used by the nervous system, immune system and in blood vessel function. Polymorphisms in this enzyme can cause reduced immune system function, exercise intolerance and fatigue. SOCS1 Suppressor of Cytokine Signaling 1 is an intracellular protein that is a member of the STAT (Signal Transducer and Activator of Transcription) family that is necessary to curb pro- inflammatory cytokine signaling. Mutations in SOCS1 are predicted to prolong inflammatory responses, thereby requiring assistance with inflammatory control. STAT4 The Signal Transducer and Activator of Transcription 4 (STAT4) gene encodes a transcription factor that responds to extracellular growth factors and cytokines. Mutations in the STAT4 gene are associated with inflammatory disorders like lupus and rheumatoid arthritis. TNF Tumor necrosis factor, TNF, is an important pro-inflammatory signaling molecule. Polymorphisms in the protein coding part of this gene are associated with more severe proinflammatory responses and require supplementation for inflammatory control. TRAF-1 TRAF1 (TNF Receptor Activation Factor 1) is produced by T cells and functions as an “off switch” for Toll like receptors and Janus Kinase. Polymorphisms of this gene are associated with chronic inflammation and can be associated with chronic Epstein Barr infections. VDR Taql The Vitamin D (calcitriol) Receptor is a member of the nuclear receptor family. Upon activation by vitamin D (a secosteroid), the VDR causes the activation or deactivation of protein production by the cell. Impaired vitamin D function can result in significant immune weakness and increased cancer risk, as well as, early bone loss, an increased risk of cognitive decline and mood disorders. Methylation is a primary' biochemical process in the body that involves the addition of a "methyl" chemical group to a vitamin or neurotransmitter. The addition of the "methy l" group allows for very specific biochemical interactions. Poor "methylation" function alters the effectiveness, delivery and function of many vitamins and important chemicals in the cell. DHFR Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. This enzyme is the second enzyme in the folic acid conversion chain. Having a mutation in this enzyme can create a methylation deficiency with a MTHFR mutation. FOLR1 Folate Receptor 1 (FOLR1) is a member of the folate receptor (FOLR) family. Members of this gene family have a high affinity for folate. Polymorphisms in this gene allow for poor delivery of folate to the interior of cells. This can create a high plasma folic acid. This polymorphism does create a methylation deficiency. This polymorphism is associated with many disorders of pregnancy. FOLR2 Folate Receptor 2 (FOLR2) is a member of the folate receptor (FOLR) family. Members of this gene family have a high affinity for folic acid. Polymorphisms in this gene allow for poor delivery of folic acid to the interior of cells. This can create a high plasma folic acid. This polymorphism does create a methylation deficiency. This polymorphism is associated with many disorders of pregnancy. This receptor is found in high quantities on the placenta, thymus and bone marrow. Can be affiliated with immune disorders. GIF The glycoprotein product of the Gastric Intrinsic Factor (GIF) gene is secreted by the stomach lining. GIF protein is required for absorption of Vitamin B12. B12 is necessary for normal red blood cell maturation. MTHFD1 Methylenetetrahydrofolate Dehydrogenase 1 enzyme handles 2 significant enzymes conversions in the production of L-MTHF. This common polymorphism causes a significant methylation deficiency due to the fact that it is utilized in two steps in methyl-folate production. MTHFR A1298C Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the bioactive form of folic acid. Two significant polymorphism variants exist in this gene, the A1298C and the C677T. The 1298 confers a conversion weakness of 10% for one copy and approximately 20% for two copies. In contrast, the 677 variant is much more severe and conveys a 40% conversion weakness for one copy and 70% for two copies. A reduced level of MTHFolate produces significant biochemical effects including poor production of dopamine and serotonin, pregnancy complications, poor healing of the nervous system, weak mitochondrial function, reduced production of glutathione, poor cell turnover and poor function of T cell lymphocytes. C677T Methylene tetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the bioactive form of folic acid. Two significant polymorphism variants exist in this gene, the A1298C and the C677T. The 1298 confers a conversion weakness of 10% for one copy and approximately 20% for two copies. In contrast, the 677 variant is much more severe and conveys a 40% conversion weakness for one copy and 70% for two copies. A reduced level of MTHFolate produces significant biochemical effects including poor production of dopamine and serotonin, pregnancy complications, poor healing of the nervous system, weak mitochondrial function, reduced production of glutathione, poor cell turnover and poor function of T cell lymphocytes. MTHFS MTHFS (methenyletetrahydrofolate synthase) is an enzyme that catalyzes the conversion of 5 -formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates. This polymorphism codes for a decreased function of the enzyme and results in poor utilization of Leucovorin (5-formyltetrahydrofolate). MTR MTR (Methionine Synthase) codes for the enzyme that catalyzes the final step in methionine biosynthesis. Polymorphisms in this gene lead to poor recycling of methionine from homocysteine. This enzyme work in coordination with MTRR and requires both MTHF and B12 for proper functioning. Deficiencies in Methionine leads to poor methylation that is associated with numerous neurological, cardiovascular and immunological disease states, as well as, infertility and birth defects. MTRR Ala637= Methionine Synthase Reductase is an enzyme responsible for the production of methionine, a very important amino acid. Polymorphisms in this enzyme require an increased amount of Methyl B12 to help this reaction. SLC19A1 The SLC19A1 gene encodes the reduced folate carrier (RFC) protein. Mutations in the RFC are associated with reduced plasma folate. TCN1 The protein product of the transcobalamin 1 (TCN1) gene binds Vitamin Bl 2 and protects it from the low pH environment of the human stomach. Individuals homozygous for the G allele of the TCN1 SNP, rs526934, are predicted to have lower serum B12. TCN2 The protein product of the Transcobalamin 2 gene, TCN2, binds the active form of vitamin B-12. Individuals with the G/G phenotype at rsl801198 have decreased serum B-12 and increased homocysteine when compared to individuals with the C/C phenotype. MITOCHONDRIA The mitochondrial enzymes are responsible for energy production from the mitochondria. The mitochondria is known as the "powerhouse" of the cell and produces over 90% of the energy for a cell. The mitochondrial respiratory chain (also known as the electron transport chain) is where these 4 protein complexes are found. Polymorphic alterations in these enzymes reduce the energy output of the mitochondria and leads to symptoms of chronic fatigue, cognitive deficiency, exercise intolerance, low metabolic rate, muscle weakness, poor healing and higher rates of sleep disorders and mood abnormalities. ATP5C1 ATPase 5cl (ATP5C1) is an enzyme responsible for producing ATP (the energy component) in the mitochondria. This protein is known as Complex V (the 5th protein) in the mitochondrial respiratory chain. Polymorphisms in the gene confer a weakened energy production by the mitochondria. COX5A Cytochrome c oxidase subunit 5 a (COX5A) is a protein in a subunit of the cytochrome c oxidase complex, also known as Complex IV of the mitochondrial electron transport chain. Polymorphisms in this enzyme produce a weakened energy production by the mitochondria. COX6C Cytochrome c oxidase subunit 6c (COX6C) is a protein in a subunit of the cytochrome c oxidase complex, also known as Complex IV of the mitochondrial electron transport chain. Polymorphisms in this enzyme produce a weakened energy production by the mitochondria. NDUFS3 The NDUFS3 genes encodes a mitochondrial enzyme, NADH Dehydrogenase (Ubiquinone) Fe-S Protein 3. Like other NDUFS proteins, NDUFS3 is thought to require ubiquinone for full activity. NDUFS7 NADH Dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDUFS7) is a mitochondrial protein also know as Complex I of the mitochondrial respiratory chain. It is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Polymorphisms in this enzyme produce a weakened energy production in the mitochondria. NDUFS8 NADH Dehydrogenase (Ubiquinone) Fe-S Protein 8 (NDUFS8) encodes an enzyme in the mitochondrial respiratory chain. Mutations in the NDUFS8 gene are associated with Leigh Syndrome, osteoporosis, and mitochondrial complex I deficiency. UQCRC2 Arg 183 Gin Ubiquinol Cytochrome c Reductase (UQCR, Complex II) is a mitochondrial enzyme protein also known as Complex III of the electron transport chain. Polymorphisms in this enzy me produce a weakened energy production by the mitochondria. NEUROTRANSMITTER Neurotransmitters are chemicals that are used to produce specific effects in the nervous system. These specific neurotransmitter genomics assess a person's risk for anxiety , depression and dysphoria. COMT V158M Catechol-O- methyltransferase (COMT) is one of several enzymes that degrade catecholamine neurotransmitters such as dopamine, epinephrine, and norepinephrine. COMT's main function is to inactivate neurotransmitters (dopamine, epinephrine, and norepinephrine) by the addition of a methyl group to the catecholamine. Normal COMT function allows people to rapidly reverse feelings of anxiety or depression. COMT (+/-) patients have sluggish ability to alter anxiety or depression episodes. COMT (+/+) patients are more prone to prolonged episodes of anxiety, depression and OCD. DBH DBH (Dopamine Beta Hydroxylase) is an oxidoreductase belonging to the copper type II, ascorbate-dependent monooxygenase family. The encoded protein, expressed in neurosecretory vesicles catalyzes the conversion of dopamine to norepinephrine, which functions as both a hormone and sympathetic nervous system function. Polymorphisms in this gene lower the production of norepinephrine which causes poor autonomic and cardiovascular function, including hypotension and ptosis. Polymorphisms in this gene have also been linked to Autism, ADD, bipolar disorder and major depression. GAD1 rs3828275 Glutamic Acid Decarboxylase (GAD 1) is the enzyme responsible for conversion of glutamic acid (a stimulant nemotransmitter) to GABA (a calming nemotransmitter). Deficiency of GABA from polymorphisms in this enzyme are associated with sleep disorders, "half glass empty" syndrome, dysphoria, and spasticity. HTR2A 5 -hydroxy tryptamine receptor 2 (HTR2) is one of the nemonal receptors for the neurotransmitter serotonin. Mutations in the HTR2 gene are associated with individual response to antidepressants, appetite, and mood. IDO1 IOD1 (indolamine 2,3 dioxygenase 1) codes for a heme enzyme that catalyzes the first and rate-limiting step in tryptophan catabolism to N-formyl-kynmenine. This enzyme acts on multiple tryptophan substrates including D-tryptophan, L-tryptophan, 5 -hydroxy -tryptophan, tryptamine, and serotonin. This enzyme is thought to play a role in a variety of pathophysiological processes such as neuropathology and immunoregulation. Buildup of tryptophan can cause apoptosis of T cells and a decrease in T regulatory cell numbers. MAOA Monoamine oxidase A (MAOA) is one of the classic nemotransmitter degradation enzymes. By degrading serotonin, dopamine, epinephrine, and norepinephrine, MAO- A ends neuronal signaling induced by those nemotransmitters. Mutations in the MAO- A gene leads to decreased degradation of these nemotransmitters and can be associated with increased aggression, mood disorders and drug addiction. MAOB Monoamine Oxidase B (MAO B) catalyzes the nemoactive amines, such as dopamine, epinephrine, norepinephrine, and plays a role in the stability of mood in the central nervous system. MAO B's primary purpose is to degrade dopamine. Patients who possess polymorphisms of MAO B have a higher risk of clinical depression and mood disorders. SLC6A4 The SLC6A4 gene encodes the serotonin transporter, also known as SERT. The serotonin transporter is responsible for clearing the serotonin neurotransmitter from the synaptic space. SERT is the target of many therapeutic drugs. Polymorphisms in the SLC6A4 gene are associated with increased risk of anxiety and depression and less effective response to SSRI medications. TPH2 TPH2 (Tryptophan Hydroxylase 2) gene catalyzes the first and rate limiting step in the biosynthesis of serotonin (5HT), an important hormone and nemotransmitter. Mutations in this gene have been shown to be associated with psychiatric diseases such as bipolar affective disorder, anxiety and major depression. Polymorphisms in this gene are also correlated to an increased response rate to SSRI medications.

The control participant did not change his lifestyle, continued abusing alcohol, engaged in gambling, and did not follow the prescribed protocol to support his biochemical pathways. The 85 biomarkers identified, isolated, and measured in the STIGMA Panel underscored the abuse to the examined biochemical pathways and the impact of leaving them untreated.

The independent participant collected buccal, saliva, and urine samples for evaluation. The genes evaluated in the sample included the following genes: C3, CD14, IL2, IL4, IL5, IL6, IL13, STAT4, TNF, TRAF1, IL23R, IL2RA, SOCS1, CTLA4, IDO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1, HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO- A, MAO-B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V. The neurotransmitters and hormones evaluated in the sample included: Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine ratio, Glutamate, Gamma-aminobutyrate, Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA.

The independent participant had the following genes with no clinical abnormality: 1L2, 1L13, 1L23R, 1L2RA, SOCS1, DRD2, ATG12, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, HLADQA2, HLADRB1, FOLR1, DHFR, MTHFS, MTHFRA1298C, MTF, MTFFA664A, MTFFA66G, FIG, TCN1, VDRTaq, GV or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, ATP5C1, MAO-A, MAO-B, CTH, AHCY, GSR, GSTM1, GSTM3, and GSTP1I105V. The following genes of the independent participant had a heterozygous result: ATG16Li, ATG16L1, HLADQA1, HLADRB2, FOLR2, MTHFD1, MTHFRC677T, SLC19A1, TCN2, COX5A, COX6C, COMTV158M, GAD1 , GAD1 , HTR2, and SLC6A4. The following genes of the independent participant had a homozygous result: CD14, TRAF1, ATG5, NOS2, and CoQ2.

The independent participant’s reference ranges for Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine Ratio, Glutamate, Gamma-aminobutyrate, Glycine, Histamine, Phenethylamine, and Creatine were 60-125 pg/gCr, 125-175 pg/gCr, 35-45 pg/gCr, 8-11 pg/gCr, <13, 15-35 pmol/gCr, 1.5-4 pmol/gCr, 450-2200 pmol/g, 10-20 pg/gCr, 30-70 nmol/gCr, and 30-225 mg/dL respectively. DHEA Saliva reference range is 200-400 pg/ml, Cortisol salivia 2-4AM reference range is <1.0 ng/ml, 7AM is 7.0-10.0 ng/ml, 12PM 3.0-6.0 ng/ml, 5PM is 2.0-4.0 ng/ml, and 10PM is <1.5 ng/ml. The independent participant’s results were as follows: Serotonin 166.7 pg/gCr, Dopamine 268 3 pg/gCr, Norepinephrine 35.6 pg/gCr, Epinephrine 13.0 pg/gCr, Norepinephrine I Epinephrine ratio 6.2, Glutamate 57.4 pmol/gCr, Gamma- aminobutyrate (GABA) 16.6 pmol/gCr, Glycine 409 pmol/g. Histamine 27.1 pg/gCr, Phenethylamine (PEA) 193.7 nmol/gCr, Creatinine 49.7 mg/dL, DHEA Saliva 176.7 pg/ml, 10:30AM Cortisol 2.2 ng/ml, 2PM Cortisol 1.0 ng/ml, 5PM Cortisol 0.6 ng/ml, and 10PM Cortisol 0.3 ng/ml. The independent participant’s Pharmacogenomic Test results did not impact her pharmaceutical use as she does not take any prescribed medications. Based on this data and information and the analysis of that data and information the independent participant was prescribed a specific protocol of nutraceuticals and pharmaceuticals.

The independent participant agreed to following the recommended protocol based on her STIGMA panel results for 6 months. The independent participant retested after 6 months and her results were as follows: genes with no clinical abnormality included IL2, IL13, IL23R, IL2RA, SOCS1, DRD2, ATG12, ATG16L1, AHCY, CTH, GSTP11105V, GSTM1, AOC1, HNMT, HNMT, FUT2, HLADQA2, HLADRB1, FOLR1, DHFR, MTHFS, MTHFRA1298C, MTF, MTFFA664A, MTFFA66G, FIG, TCN1, VDRTaq, GV or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, ATP5C1, MAO-A, MAO-B, CTH, AHCY, GSR, GSTM1, GSTM3, and GSTP1I105V. The following genes had a heterozygous result: ATG16Li, ATG16L1, HLADQA1, HLADRB2, FOLR2, MTHFD1, MTHFRC677T, SLC19A1, TCN2, COX5A, COX6C, COMTV158M, GAD1, GAD1, HTR2, and SLC6A4. The following genes had a homozygous result: CD14, TRAF1, ATG5, NOS2, and CoQ2. The detoxification enzymes are responsible for clearing environmental chemicals and metabolites from our body. Accumulation of these chemicals and by-products can damage intracellular biochemical functions. Alterations in these systems can have a significant negative effect on the nervous system and immune systems functions. These polymorphisms can result in decreased "quality of life" and even decreased "life-span". AHCY Adenosylhomocysteinase (AHCY) is an enzyme that breaks down S- adenosylhomocysteine (SAH) to homocysteine and adenosine. Polymorphisms in this gene will lead to lower levels of homocysteine and glutathione. CTH Glutathione production is dependent on the function of the enzyme cystathionine gamma-lyase (CTH). CTH converts cystathionine to cysteine. Individuals with mutations in the CTH gene are predicted to have decreased glutathione -mediated detoxification. GSR The glutathione reductase (GSR) gene encodes a protein involved in metabolizing glutathione. Mutations in this gene are associated with impaired cellular redox homeostasis. GSTM1 Glutathione S-transferase Ml (GSTM1) is an important enzyme in the body's detoxification pathway. GSTM1 conjugates glutathione to molecules (drugs, environmental toxins, carcinogens etc.) bound for excretion. GSTM1 is mainly responsible for binding toxins in joints and for binding carcinogens. GSTM3 Glutathione S-transferase mu 3 is an enzyme that detoxifies drugs, environmental toxins, and carcinogens by conjugating toxins to glutathione and subsequent excretion by the kidneys. Mutations in GSTM3 are associated with decreased clearance of toxins, anesthetics and drugs from the nervous system. GSTP1 Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification. The glutathione S-transferase pi gene (GSTP1) functions in chemical clearance and anti-inflammatory propenties. High concentration of GST-p are found in the skin, lungs, sinuses, bladder and the intestinal tract. Polymorphisms of this enzyme allow for increased inflammatory activity in these areas that include eczema, asthma, chronic sinusitis, IBS, "leaky" gut and interstitial cystitis. DEVELOPMENTAL The SNPs in this category have been identified as potential areas of weakness in the recovery' of developmental disorders. ATG12 Autophagy-related 12 protein is part of the core autophagy' machinery inside the cell. Autophagy, a form of cellular "recycling" is necessary for many cell functions. ATG12 is specifically involved in turning off the innate immune response. Mutations in the ATG12 gene are predicted to lead to increased activity of the innate immune response, and overall inflammation. ESSENTIAL VITAMINS The polymorphisms in this panel will identify any potential weakness of absorption, conversion or delivery or your essential vitamins. COQ2 CoQ2 (Para-hydroxybenzoate — polyprenyltransferase, mitochondrial) codes for an enzyme that functions in the final steps in the biosynthesis of CoQlO (ubiquinone).. This enzyme, which is part of the coenzyme Q10 pathway, catalyzes the prenylation of parahydroxybenzoate with an all-trans poly prenyl group. Mutations in this gene cause coenzyme Q10 deficiency. Polymorphisms in this gene can lead to severe fatigue, muscle weakness, exercise intolerance and general mitochondrial weakness. GC or DBP GC aka DBP (Vit. D Binding Protein) gene codes for Vit. D binding protein. This protein belongs to the albumin family and is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It is manufactured in the hepatic parenchymal cells. DBP is capable of binding to all forms of Vit D including ergocalciferol (vitamin D2) and cholecaldiferol (vitamin D3), the 25 -hydroxylated forms (calcifediol) and the active hormonal product, 1,25- dihydroxyvitamin D (calcitriol). The major proportion of vitamin D in blood is bound to this protein. It transports vitamin D metabolites between skin, liver and kidney, and then on to the various target tissues. It binds to vitamin D and its plasma metabolites and transports them to target tissues. Polymorphisms in this gene decrease the affinity of the protein to Vit. D which reduces the response rate to Vit. D therapy. Patients with these polymorphisms require high doses of Vit D supplementation. INFLAMMATORY This Enzy me category has significant effects on the inflammatory state of a person's body. Polymorphisms in these specific enzymes will significantly increase the levels of inflammation in the body. By supplementing these enzyme deficiencies, the patient will effectively reduce inflammatory damage to the body. AOC1 The SNP rs 10156191 encodes a weaker form of the histamine degradation enzyme Amine Oxidase, Copper Containing 1 (AOC1). This mutation, Thrl6Met, is predicted to produce an enzyme with less catalytic activity and associated higher levels of pro-inflammatory amines like histamine and putrescine. ATG16L1 rs 10210302 The ATG16L1 gene encodes a protein that is a vital component of a protein complex necessary for the cellular phenomena known as autophagy. Autophagy is the process of degrading and cleaning of inert debris of the cell. Weakness in autophagy leads to abnormal accumulation of cellular “garbage” that will eventually affect the cellular function and lead to autophagy-related disease states in including many neurological and immunological diseases, DM Type 2 and fatty liver disease. ATG5 Autophagy -related 5 protein (ATG5) is an important intracellular mediator of the autophagy response. ATG5 is involved in a wide range of "quality control" features inside the cell: autophagy vesicle formation, innate immune system signaling, consumption of damaged mitochondria, and apoptosis. Mutations in the ATG5 gene are associated with numerous neurological, immunological and endocrine syndromes. C3 Essential for the immune response, C3 is a protein involved in initiation of the complement system. C3 polymorphisms are associated with susceptibility to asthma and other inflammatory disorders. The CD 14 protein is a macrophage cell surface receptor that binds bacterial cell wall components. As one of the initiators of the innate immune response, fully functional CD 14 is necessary for normal response to potential pathogens. Mutations in the CD 14 gene are associated with susceptibility to asthma and other allergen-mediated inflammatory processes. CTLA4 Cytotoxic T- lymphocyte Associated protein 4 (CTLA4) is an important inhibitor of T-cell activity: CTLA4 is part of the signaling cascade that turns off overactive T cells. Mutations in the gene that encodes CTLA4 are associated with a host of diseases characterized by a heightened immune state. DRD2 Dopamine receptor D2 is an important component of the nemoinflammation process. Activation of DRD2 signaling is thought to decrease TNFalpha release from inflammatory mast cells. Polymorphisms associated with decreased DRD2 signaling activity are predicted to lead to pro -inflammatory phenotypes. FUT2 Fucosyltransferase 2 (FUT2) is responsible for producing specific sugar groups that are secreted by the intestinal cells into the bowel to attract "good bacteria" . Polymorphisms in this gene produce "poor secreter" status. Lack of these sugars allows for gut dysbiosis and a higher risk of inflammatory bowel disease. HLA-DQA1 Major histocompatibility complex, DQ alpha 1 (HLA-DQA1) is a human gene responsible for a cell surface receptor essential to the function of the immune system. Patients with a polymorphism in this gene are at higher risk for auto-immune based inflammatory disease including Celiac disease, Crohn's, Ulcerative Colitis, and gluten sensitivity. HLA- DQA2 Major histocompatibility complex, DQ alpha 2 (HLA-DQA2) is a human gene responsible for a cell surface receptor essential to the function of the immune system. Patients with a polymorphism in this gene are at higher risk for auto-immune based inflammatory disease including Celiac disease, Crohn's, Ulcerative Colitis, and gluten sensitivity. HLA-DRB1 Human leukocyte antigen DRB1 (HLA-DRB1) is an important mediator of the adaptive immune system. HLA-DRB1 protein "presents" antigens from invading pathogens to other cells in the immune system. Mutations in this gene are associated with higher risk of auto-immunity and other chronic inflammatory diseases. HLA-DRB2 Human leukocyte antigen DRB2 (HLA-DRB2) is a cell surface receptor involved in mediating the adaptive immune response. Mutations in HLA-DRB2 are associated with susceptibility to chronic inflammation and decreased ability to recover from toxic mold exposure. HMNT rsl2995000 The HNMT gene encodes the histamine degradative enzyme, histamine N- methyltransferase. HNMT, in contrast to AOC1, requires the methyl donor S-adenosylmethionine and a complete methylation pathway for normal function. Polymorphisms in HNMT gene expression or proteincoding are predicted to prolong the pro -inflammatory effects of histamine signaling. HNMT Thrl05Ile The HNMT gene encodes the histamine degradative enzyme, histamine N-methyltransferase. HNMT, in contrast to AOC1, requires the methyl donor S-adenosylmethionine and a complete methylation pathway for normal function. Polymorphisms in HNMT gene expression or protein coding are predicted to prolong the pro- inflammatory effects of histamine signaling. IL13 IL13 (Interleukin 13) is a member of the interleukin family of chemical messengers of the immune system. Polymorphisms in this gene are associated with changes in IL 13 gene expression and increase the risk of more severe inflammatory responses to allergens. IL2 IL2 (Interleukin 2) codes for a secreted cytokine that is important for the proliferation of T and B lymphocytes. The receptor of this cytokine by interleukin 4 (IL4). Overall, the polymorphism of IL4 produces a robust inflammatory response to allergic stimuli which can be associated with severe allergic symptoms, immune cancer risk and bowel inflammation. IL23R A/A and A/G genotypes at rs 11209026, a polymorphism in the Interleukin 23 Receptor gene (IL23R), provide a protective effects against Crohn's disease. IL2RA Polymorphisms in a non-protein coding region of the Interleukin 2 Receptor subtype A (IL2RA) are associated with increased risk of multiple sclerosis in some populations. 1L4 IL4 (Interleukin 4) codes for a pleiotropic cytokine produced by activated T cells. The interleukin 4 receptor also binds to IL13, which may contribute to many overlapping functions of this cytokine and IL 13. The STAT system, a signal transducer and activator of transcription, has been shown to play a central role in mediating the immune regulatory signal of this cytokine. Overall, the polymorphism of IL4 produces a robust inflammatory response to allergic stimuli which can be associated with severe asthma, allergies, chronic sinusitis, as well as, migraines and bowel inflammation. IL5 The protein product of the Interleukin 5 gene (IL5) is important for normal development of B lymphocytes and eosinophils (a pro -inflammatory white blood cell). Inactivating mutations in the IL5 gene are associated with susceptibility to certain viral infections and increased aggression of inflammatory response. These polymorphisms are also associated with increased aggression of allergies, asthma and eosinophilia. IL6 Interleukin 6, IL6, is an important pro-inflammatory cytokine. Polymorphisms in this gene leads to a more aggressive inflammatory response. Patients with IL-6 mutations require assistance with inflammatory control. NOS2 Nitric Oxide Synlhanse 2 (NOS2) is responsible for producing nitric oxide, a biologic mediator used by the nervous system, immune system and in blood vessel function. Polymorphisms in this enzyme can cause reduced immune system function, exercise intolerance and fatigue. SOCS1 Suppressor of Cytokine Signaling 1 is an intracellular protein that is a member of the STAT (Signal Transducer and Activator of Transcription) family that is necessary to curb pro-inflammatory cytokine signaling. Mutations in SOCS1 are predicted to prolong inflammatory responses, thereby requiring assistance with inflammatory control. STAT4 The Signal Transducer and Activator of Transcription 4 (STAT4) gene encodes a transcription factor that responds to extracellular growth factors and cytokines. Mutations in the STAT4 gene are associated with inflammatory disorders like lupus and rheumatoid arthritis. TNF Tumor necrosis factor, TNF, is an important pro-inflammatory signaling molecule. Polymorphisms in the protein coding part of this gene are associated with more severe proinflammatory responses and require supplementation for inflammatory control. TRAF-1 TRAF1 (TNF Receptor Activation Factor 1) is produced by T cells and functions as an “off switch” for Toll like receptors and Janus Kinase. Polymorphisms of this gene are associated with chronic inflammation and can be associated with chronic Epstein Barr infections. VDR Taql The Vitamin D (calcitriol) Receptor is a member of the nuclear receptor family. Upon activation by vitamin D ( a secosteroid), the VDR causes the activation or deactivation of protein production by the cell. Impaired vitamin D function can result in signigicant immune weakness and increased cancer risk, as well as, early bone loss, an increased risk of cognitive decline and mood disorders. Methylation is a primary biochemical process in the body that involves the addition of a "methyl" chemical group to a vitamin or neurotransmitter. The addition of the "methyl" group allows for very specific biochemical interactions. Poor "methylation" function alters the effectiveness, delivery and function of many vitamins and important chemicals in the cell. DHFR Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. This enzyme is the second enzyme in the folic acid conversion chain. Having a mutation in this enzyme can create a methylaiton deficiency with a MTHFR mutation. FOLR1 Folate Receptor 1 (FOLR1) is a member of the folate receptor (FOLR) family. Members of this gene family have a high affinity for folate. Polymorphisms in this gene allow for poor delivery of folate to the interior of cells. This can create a high plasma folic acid. This polymorphism does create a methylation deficiency. This polymorphism is associated with many disorders of pregnancy. FOLR2 Folate Receptor 2 (FOLR2) is a member of the folate receptor (FOLR) family. Members of this gene family have a high affinity for folic acid. Polymorphisms in this gene allow for poor delivery of folic acid to the interior of cells. This can create a high plasma folic acid. This polymorphism does create a methylation deficiency. This polymorphism is associated with many disorders of pregnancy. This receptor is found in high quantities on the placenta, thymus and bone marrow. Can be affiliated with immune disorders. GIF The glycoprotein product of the Gastric Intrinsic Factor (GIF) gene is secreted by the stomach lining. GIF protein is required for absorption of Vitamin B12. B12 is necessary for normal red blood cell maturation. MTHFD1 Methylenetetrahydrofolate Dehydrogenase 1 enzyme handles 2 significant enzymes conversions in the production of L-MTHF. This common polymorphism causes a significant methylation deficiency due to the fact that it is utilized in two steps in methyl-folate production. MTHFR A1298C Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the bioactive form of folic acid. Two significant polymorphism variants exist in this gene, the A1298C and the C677T. The 1298 confers a conversion weakness of 10% for one copy and approximately 20% for two copies. In contrast, the 677 variant is much more severe and conveys a 40% conversion weakness for one copy and 70% for two copies. A reduced level of MTHFolate produces significant biochemical effects including poor production of dopamine and serotonin, pregnancy complications, poor healing of the nervous system, weak mitochondrial function, reduced production of glutathione, poor cell turnover and poor function of T cell lymphocytes. MTHFR C677T Methylene tetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, the bioactive form of folic acid. Two significant polymorphism variants exist in this gene, the A1298C and the C677T. The 1298 confers a conversion weakness of 10% for one copy and approximately 20% for two copies. In contrast, the 677 variant is much more severe and conveys a 40% conversion weakness for one copy and 70% for two copies. A reduced level of MTHFolate produces significant biochemical effects including poor production of dopamine and serotonin, pregnancy complications, poor healing of the nervous system, weak mitochondrial function, reduced production of glutathione, poor cell turnover and poor function of T cell lymphocytes. MTHFS MTHFS (methenyletetrahydrofolate synthase) is an enzyme that catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates. This polymorphism codes for a decreased function of the enzyme and results in poor utilization of Leucovorin (5-formyltetrahydrofolate).. MTR MTR (Methionine Synthase) codes for the enzyme that catalyzes the final step in methionine biosynthesis. Polymorphisms in this gene lead to poor recycling of methionine from homocysteine. This enzyme work in coordination with MTRR and requires both MTHF and B12 for proper functioning. Deficiencies in Methionine leads to poor methylation that is associated with numerous neurological, cardiovascular and immunological disease states, as well as, infertility and birth defects. MTRR Ala637= Methionine Synthase Reductase is an enzyme responsible for the production of methionine, a very important amino acid. Polymorphisms in this enzyme require an increased amount of Methyl B12 to help this reaction. SLC19A1 The SLC19A1 gene encodes the reduced folate carrier (RFC) protein. Mutations in the RFC are associated with reduced plasma folate. TCN1 The protein product of the transcobalamin 1 (TCN1) gene binds Vitamin B12 and protects it from the low pH environment of the human stomach. Individuals homozygous for the G allele of the TCN1 SNP, rs526934, are predicted to have lower serum B12. TCN2 The protein product of the Transcobalamin 2 gene, TCN2, binds the active form of vitamin B-12. Individuals with the G/G phenotype at rsl801198 have decreased serum B-12 and increased homocysteine when compared to individuals with the C/C phenotype. MITOCHONDRIA The mitochondrial enzymes are responsible for energy production from the mitochondria. The mitochondria is known as the "powerhouse" of the cell and produces over 90% of the energy for a cell. The mitochondrial respiratory chain (also known as the electron transport chain) is where these 4 protein complexes are found. Polymorphic alterations in these enzymes reduce the energy output of the mitochondria and leads to symptoms of chronic fatigue, cognitive deficiency, exercise intolerance, low metabolic rate, muscle weakness, poor healing and higher rates of sleep disorders and mood abnormalities. ATP5C1 ATPase 5cl (ATP5C1) is an enzyme responsible for producing ATP (the energy component) in the mitochondria. This protein is known as Complex V (the 5th protein) in the mitochondrial respiratory chain. Polymorphisms in the gene confer a weakened energy production by the mitochondria. COX5 A Cytochrome c oxidase subunit 5 a (COX5A) is a protein in a subunit of the cytochrome c oxidase complex, also known as Complex IV of the mitochondrial electron transport chain. Polymorphisms in this enzyme produce a weakened energy production by the mitochondria. COX6C Cytochrome c oxidase subunit 6c (COX6C) is a protein in a subunit of the cytochrome c oxidase complex, also known as Complex IV of the mitochondrial electron transport chain. Polymorphisms in this enzyme produce a weakened energy production by the mitochondria. NDUFS3 The NDUFS3 genes encodes a mitochondrial enzyme, NADH Dehydrogenase (Ubiquinone) Fe-S Protein 3. Like other NDUFS proteins, NDUFS3 is thought to require ubiquinone for full activity. NDUFS7 NADH Dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDUFS7) is a mitochondrial protein also know as Complex I of the mitochondrial respiratory chain. It is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Polymorphisms in this enzyme produce a weakened energy production in the mitochondria. NDUFS8 NADH Dehydrogenase (Ubiquinone) Fe-S Protein 8 (NDUFS8) encodes an enzyme in the mitochondrial respiratory chain. Mutations in the NDUFS8 gene are associated with Leigh Syndrome, osteoporosis, and mitochondrial complex I deficiency. UQCRC2 Arg 183 Gin Ubiquinol Cytochrome c Reductase (UQCR, Complex II) is a mitochondrial enzyme protein also known as Complex III of the electron transport chain. Polymorphisms in this enzyme produce a weakened energy production by the mitochondria. NEUROTRANSMITTER Neurotransmitters are chemicals that are used to produce specific effects in the nervous system. These specific neurotransmitter genomics assess a person's risk for anxiety, depression and dysphoria. COMT V158M Catechol-O- methyltransferase (COMT) is one of several enzymes that degrade catecholamine neurotransmitters such as dopamine, epinephrine, and norepinephrine. COMT's main function is to inactivate neurotransmitters (dopamine, epinephrine, and norepinephrine) by the addition of a methyl group to the catecholamine. Normal COMT function allows people to rapidly reverse feelings of anxiety or depression. COMT (+/-) patients have sluggish ability to alter anxiety or depression episodes. COMT (+/+) patients are more prone to prolonged episodes of anxiety, depression and OCD. GAD1 rs3828275 Glutamic Acid Decarboxylase (GAD 1) is the enzyme responsible for conversion of glutamic acid (a stimulant neurotransmitter) to GABA (a calming neurotransmitter). Deficiency of GABA from polymorphisms in this enzyme are associated with sleep disorders, "half glass empty" syndrome, dysphoria, and spasticity. HTR2A 5-hydroxytryptamine receptor 2 (HTR2) is one of the neuronal receptors for the neurotransmitter serotonin. Mutations in the HTR2 gene are associated with individual response to antidepressants, appetite, and mood. IDO1 IOD1 (indolamine 2,3 dioxygenase 1) codes for a heme enzyme that catalyzes the first and rate-limiting step in tryptophan catabolism to N-formyl-kynurenine. This enzyme acts on multiple tryptophan substrates including D- tryptophan, L-tryptophan, 5 -hydroxy -tryptophan, tryptamine, and serotonin. This enzyme is thought to play a role in a variety of pathophysiological processes such as neuropathology and immunoregulation. Buildup of tryptophan can cause apoptosis of T cells and a decrease in T regulatory cell numbers. MAOA Monoamine oxidase A (MAOA) is one of the classic neurotransmitter degradation enzymes. By degrading serotonin, dopamine, epinephrine, and norepinephrine, MAO-A ends neuronal signaling induced by those neurotransmitters. Mutations in the MAO-A gene leads to decreased degradation of these neurotransmitters and can be associated with increased aggression, mood disorders and drug addiction. MAOB Monoamine Oxidase B (MAO B) catalyzes the neuroactive amines, such as dopamine, epinephrine, norepinephrine, and plays a role in the stability of mood in the central nervous sy stem. MAO B's primary purpose is to degrade dopamine. Patients who possess polymorphisms of MAO B have a higher risk of clinical depression and mood disorders. SLC6A4 The SLC6A4 gene encodes the serotonin transporter, also known as SERT. The serotonin transporter is responsible for clearing the serotonin neurotransmitter from the synaptic space SERT is the target of many therapeutic drugs. Polymorphisms in the SLC6A4 gene are associated with increased risk of anxiety and depression and less effective response to SSRI medications.

No changes in genetic single nucleotide polymorphisms were expressed, however significant optimization of the independent’s neurotransmitters and hormones were noted. The Independent’s reference ranges for Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine Ratio, Glutamate, Gammaaminobutyrate, Glycine, Histamine, Phenethylamine, and Creatine were 60-125 pg/g, 125-250 pg/g, 22-50 pg/g, 1.6-8.3 pg/g, <13, 12.0-45.0 pmol/g, 12.0-5.6 pmol/g, 450-2200 pmol/g, 14-44 pg/g, 32-84 nmol/g, and 30-225 mg/dL respectively. DHEA Saliva reference range is 200-400 pg/ml, Cortisol salivia 2-4AM reference range is <1.0 ng/ml, 7AM is 7.0-10.0 ng/ml, 12PM 3.0-6.0 ng/ml, 5PM is 2.0-4.0 ng/ml, and 10PM is <1.5 ng/ml. Her results were as follows: Serotonin 69.2 pg/g, Dopamine 188 pg/g, Norepinephrine 18.8 pg/g, Epinephrine 3.6 pg/g, Norepinephrine / Epinephrine ratio 5.2, Glutamate 17 pmol/g, Gamma-aminobutyrate (GABA) 3.3 pmol/g, Glycine 673 pmol/g, Histamine 17 pg/g, Phenethylamine (PEA) 102 nmol/g, and Creatinine 60.5 mg/dL, DHEA Saliva 95 pg/ml, 10:30AM Cortisol 6.7 ng/ml, 2PM Cortisol 2.5 ng/ml, 5PM Cortisol 2.5 ng/ml, and 10PM Cortisol 0.99 ng/ml.

Of the 16 neurotransmitters and hormones measured for the independent participant, 11 showed optimizations after following the prescribed protocol to support the biochemical pathways identified, isolated, and measured in the STIGMA Panel. Serotonin, Dopamine, Gamma-aminobutyrate (GABA), Glutamate, Phenethylamine (PEA), Histamine, Creatine, and Cortisol improved to more optimal levels through the hyper-precise prescription of nutraceuticals and pharmaceuticals to support the appropriate biochemical pathways with dosage specific to the individual. Urinary neurotransmitter levels provide an overall assessment of the body's ability to make and break down neurotransmitters and are representative of whole body levels. Neurotransmitters are secreted all through the body, in neurons of both the central and peripheral nervous systems. The enzymes, cofactors and precursors in neurotransmitter metabolism in general are the same in the periphery and in the central nervous system. Therefore, alterations in urinary neurotransmitter levels assessed in urine provide important clinical information, and may be associated with many symptoms including cognitive and mood concerns, diminished drive, fatigue and sleep difficulties, cravings, addictions and pain. Low range serotonin may contribute to mood concerns including anxiety, OCD, depression, anger and a sense of discontentment. Low range serotonin may also be associated with poor sleep quality and appetite changes, as well as chronic fatigue, rheumatoid arthritis, and over-all lassitude. Failure to regenerate tetrahydrobiopterin [BH4], an essential cofactor for serotonin synthesis, may decrease serotonin levels, and could be reflected in urine. BH4 regeneration may be supported by folates, vitamin B3, C, molybdenum and zinc. Additionally, production of serotonin requires vitamin D, iron and vitamin B6. Tryptophan is the essential precursor of serotonin. 5-HTP may increase serotonin, and L-theanine may affect serotonin function. Low norepinephrine may be associated with depression and mood changes as well as fatigue, difficulty concentrating, decreased ability to stay focused on tasks and diminished sense of personal/professional drive. Norepinephrine is converted from dopamine requiring vitamin C, copper and B3, and L-tyrosine is an amino acid precursor. L-theanine and Mucuna pruriens may modulate norepinephrine effects. Elevated phenethylamine (PEA) may contribute to anxiety, with very high levels having amphetamine -like effects. Elevations in PEA may occur due to supplementation, use of monoamine oxidase inhibitors or antipsychotic medications, high protein diets, and production by proteinfermenting gut microbes. PEA and other trace amines are found in fermented foods (wine, cheese, chocolate, etc.). Elevated PEA levels may be associated with higher cortisol levels.

The support and optimization of these pathways corroborated the independent participant’s self-reported symptomatic relief of obsession and cravings as they pertained to alcohol and opiates. In order to address the biochemical pathways requiring support, eight (8) nutraceuticals were utilized: AdreCore, Focus DL, TravaCor, Methyl Folate Plus, D-Chiro-Inositol, N.A.S. Enhancer, PEA Soothe Support, and Mito Cell PQQ. AdreCor supports catecholamines that play a role in mood, energy, memory, attention and cognition.2-5 Catecholamines are involved in the central and peripheral stress responses. Focus DL contains the precursor to PEA, a neuromodulator important for focus, cognition, and catecholamine activity. TravaCor supports GABA-A agonist activity, glutamate receptor antagonist, serotonin synthesis, and melatonin synthesis. Methyl Folate Plus supports the methylation pathway and provides adequate Folic Acid and methyl folate (5- MTHF). D-Chiro-Inositol boosts autophagy which is an essential part of clearing the debris from cells and provide better cellular performance and works as a messenger for serotonin and dopamine. N.A.S. Enhancer activates the leucine zipper protein in the NRF2 genetic pathway to enhance glutathione production; down regulates the mTOR system of the cell and activates autophagy; provides maximum assistance with antioxidant neutralization within the cell. PEA Soothe Support supports palmitoylethanolamide which is involved in a variety of cellular functions in chronic pain and inflammation. PEA has an affinity for the cannabinoid-like G-coupled receptors, which is why it is often referred to as a non-psychoactive “indirect endocannabinoid.” Mito Cell PQQ is next-generation coenzyme is being used called pyrroloquinoline quinone or PQQ that has been shown to induce mitochondrial biogenesis — the growth of new mitochondria in aging cells. While CoQlO optimizes mitochondrial function, PQQ activates genes that govern mitochondrial reproduction, protection, and repair.

In conclusion, the STIGMA Panel of the present invention accurately identified, isolated, and measured 85 biomarkers associated with addiction and addiction symptoms. When hypcr-prccisc treatment informed by the STIGMA Panel findings was prescribed and adhered to, the newly supported biochemical pathways alleviated the obsession and compulsion associated with substance use disorders.

In one embodiment, the present invention may incorporate in a device that automates the diagnosis, prognosis and treatment of numerous diseases including addictions. For example in one embodiment, the personal information of patient is provided to a patient database in the form of the results of a questionnaire filled in by the patient at a terminal. This questionnaire could include a series of questions relating to aspects of the patient's behavior or habits that are relevant to the therapeutic regime desired. The personal information could also include information relating to the patient himself. For example, it could relate to the ethnicity of the patient, the patient's weight, height, body mass index results or any other characteristic of the user of the user's lifesty le that is relevant to the determination of the optimum therapeutic regime for the patient. It will be appreciated that in other embodiments, tire personal information may be obtained in other ways, such as over a remote input device or in an interview. Once completed, the results of the questionnaire could be sent from the terminal to the patient database. The unpopulated questionnaire could be provided by the determination processor to the terminal over the communications network. Alternatively, the questionnaire could be provided by another method, such as on a storage device from to the user. A sample is taken from the patient and may be collected from buccal, saliva, and urine. The samples are then sent for analysis of numerous biomarkers. The analysis may among other things show levels of neurotransmitters and hormones and gene quality, mutations and abnormalities involved in one or more specific diseases or conditions, including the physiological triangle of addiction. Recording the information from the numerous biomarkers into a biomarker database, wherein the biomarkers include neurotransmitters, hormones concentrations and mutations in one or more genes. Specific neurotransmitters and hormones include Serotonin, Dopamine, Norepinephrine, Epinephrine, Norepinephrine/Epinephrine ratio, Glutamate, Gamma-aminobutyrate. Glycine, Histamine, Phenethylamine, Creatinine, Cortisol AM20, Cortisol Noon, Cortisol Evening, Cortisol Night, and DHEA. Specific nonlimiting list of genes include genes that code for C3, CD14, IL2, IL4, IL5, IL6, IL13, STAT4, TNF, TRAF1, IL23R, IL2RA, SOCS1, CTLA4, IDO1, DRD2, ATG5, ATG12, ATG16L1, ATG16L1, AHCY, CTH, GSTP1I105V, GSTM1, AOC1, HNMT, HNMT, FUT2, NOS2, HLADQA1, HLADQA2, HLADRB1, HLADRB2, FOLR1, FOLR2, DHRF, MTHFS, MTHFD1, MTHFRA1298C, MTHRC677T, MTF, MTRRA664A, MTRRA66G, GIF, TCN1, TCN2, VDRTaq, GC or DBP, NDUFS3, NDUFS7, NDUFS8, UQCRC2, UQCRC2, COX5A, COX6C, ATP5C1, CoQ2, COMPTV158M, GAD1, GAD1, MAO-A, MAO-B, HTR2, SLC6A4, CTH, AHCY, GSR, GSTM1, GSTM3, GSTP1I105V. The information from the biomarker database is compared to a biomarker standard and from tire comparison a deficiency is determined. In some instances the patient database is also used to determine the deficiency. The deficiency is evaluated and an optimum therapeutic regime for the patient is determined. The optimum therapeutic regime. In some embodiments the genetic testing is performed at genetic testing facility on the sample from the patient. The sample could be obtained by the patient himself with a suitable home test kit, or by a medical practitioner or otherwise. The sample would then be sent to the genetic testing facility for analysis. The results of the analysis are sent to the biomarker database via the network . Alternatively, the results could be sent on a storage device on any other suitable delivery method. The determination processor is arranged to query the patient database to obtain the personal information of the patient as well as the biomarker database. The determination processor obtains genetic criteria and personal criteria relevant to the therapeutic regime desired by the patient. This is done by comparing the genetic information and personal information of the patient with information stored in the determination database. The determination database stores a set of rules that are relevant to the therapeutic regime. For example, the determination database could store information relating to which type of lifestyles (e g. sedentary, active etc) are best suited to which therapeutic regimes. Furthermore, determination database could store information relating to genetic information that indicates that one therapeutic regime would be preferable over one or more other therapeutic regimes. The determination processor then uses the information in the determination database to obtain genetic criteria and personal criteria relevant to the therapeutic regime desired by the patient. The determination processor then combines the genetic criteria with the personal criteria in order to determine a personalized therapeutic regime for the patient. This again is done by using information stored in the determination database. For example, the determination database could store a set of rules that cause determination processor to apply different weightings to different elements of the personal criteria and the genetic criteria. This could be done in the form of a decision matrix stored on determination database and populated for the individual patient by the determination processor. Once the personal criteria and the genetic criteria have been combined in this way, the determination processor determines the personalized therapeutic regime for the patient. This personalized therapeutic regime is therefore highly tailored, because it takes into account both the patient's genetic makeup and information relating to the patient and the patient's lifestyle. In this embodiment, the determination processor then provides information relating to the personalized therapeutic regime via the network to the terminal of a doctor responsible for the patent. It will be appreciated, however, that this information could be provided to tire doctor in other ways. The doctor would then provide any medication or medical advice to the patient required by the personalized therapeutic regime. Alternatively, the determination processor could provide the information relative to the personalized therapeutic regime via the network to the terminal of the patient, or some other content delivery method from the determination network to the patient. This would allow the patient to carry out the personalized therapeutic regime without the need to consult a doctor. This could be beneficial in circumstances in which the personalized therapeutic regime relates to medications available over the counter in a phannacy or when the personalized therapeutic regime relates to a desired behavioral change in the patient.

The genetic analysis may be a genotypic analysis, but can also be proteomic analysis, as this can still provide sufficient information to identify suitable therapies, for instance based on proteins with altered function or specificity. Accordingly, sources of genetic information are not only polynucleic acids, such as DNA and/or RNA, but it is also the case that amino acids or polypeptides can also be analyzed to obtain information on the patient.

Protein isotypes may be detectable by functional assays, particularly if the protein is an enzyme. They may also be detectable by antibodies or other recognition molecules, as any alteration in protein sequence may lead to a discernible conformational change, for instance.

In some embodiments, the method includes assessing more than one of each of the following: genomic, proteomic, biochemical or metabolomic information and/or combinations thereof. For instance, information from two genomic and one metabolomic or one proteomic and one biochemical indicia or markers may be assessed.

In some embodiments, any treatment that requires pharmaceutical or non-pharmaceutical medication and ‘management' over the course of treatment is envisaged in relation to improving the curative treatment process.

The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.