PHYSICIAN

GUIDE TO GENETIC TESTING

TABLE OF CONTENTS
SECTION MULTI-TEST REPORT INTERPRETATION GUIDE CYP450-2C9 & VKORC1 SINGLE REPORT INTEREPRETATION GUIDE CYP450-2C19 SINGLE REPORT INTEREPRETATION GUIDE CYP450-2D6 SINGLE REPORT INTEREPRETATION GUIDE CYP450-3A4/3A5 SINGLE REPORT INTEREPRETATION GUIDE THROMBOSIS PANEL SINGLE REPORT INTEREPRETATION GUIDE CYP450-2C9 & VKORC1 GENOTYPING INTEREPRETATION SUMMARY CYP450-2C19 GENOTYPING INTEREPRETATION SUMMARY CYP450-2D6 GENOTYPING INTEREPRETATION SUMMARY CYP450-3A4/3A5 GENOTYPING INTEREPRETATION SUMMARY THROMBOSIS RISK TEST GENOTYPING INTEREPRETATION SUMMARY PAGE NUMBER 3-4 5 6 7 8 9 10 11 12 13 14-15

Genetic Test Results

Patient Name: Robert Simone Referrer: Dr. Tommy Brown Date Collected: 5/1/2012

Date of Birth: 10/11/1963 Sample Type: Buccal Swab Date Received: 5/2/2012

NMTC Laboratory #: 15875

Laboratory Director: Vincent Aoki, Ph.D., HCLD (ABB) Natural Molecular Testing Corp.

TEST RESULTS
Assay: CYP450-2C19
*2 Normal *3 Normal

Genotype: *1/*1
*4 Normal *5 Normal

Phenotype: Normal Metabolizer

*6 Normal *7 Normal *8 Normal *9 Normal *10 Normal

Date Reported: 5/4/2012

*13 Normal *17 Normal

InterpretaJve Guide to the MulJ-Test GeneJc Report (Page 1)

1. This is the test result. It shows both the genotype (*1/*1) and phenotype (Normal Metabolizer). For drug sensiJvity geneJc tesJng, the phenotype tells you how well the paJent will metabolize drugs for the pathway being tested. Each assay in the report has a corresponding test result indicaJng the paJents genotype and phenotype for each enzyme tested.

Assay: CYP450-2C9

Genotype: *1/*1
*2 Normal

Phenotype: Normal Metabolizer

*3 Normal

Date Reported: 5/4/2012

Assay: VKORC1

Genotype: G/A

Phenotype: Intermediate Warfarin Sensitivity

-1639G>A Intermediate S ensitivity Heterozygote(G/A)

Date Reported: 5/4/2012

Assay: CYP450-2D6
*2 Normal *3 Normal *4 Normal

Genotype: *1/*1
*6 Normal *7 Normal

Phenotype: Normal Metabolizer

*8/*14 Normal *9 Normal *10 Normal *12 Normal *17 Normal *29 Normal -1584C>G Normal *41 Normal

Date Reported: 5/4/2012

CNV (*XN) Normal CNV (*5) Normal

Assay: CYP450-3A4
*12 Normal

Genotype: *1/*1
*2 Normal

Phenotype: Normal Metabolizer

*1B Normal *17 Normal

Date Reported: 5/4/2012

*3 Normal

Assay: CYP450-3A5
*1D *1D-Mutant

Genotype: *1D/*1D/*3/*3
*2 Normal *3B

Phenotype: Poor Metabolizer

*6 Normal *7 Normal *8 Normal *9 Normal

Date Reported: 5/4/2012

*3 *3-Mutant

Normal

THROMBOSIS PANEL Assay: FACTOR V LEIDEN Genotype: G/G Phenotype: Normal Thrombosis Risk
1691 G>A G/G

Date Reported: 5/4/2012

Assay: Genotype: FACTOR II PROTHROMBIN G/G

Phenotype: Normal Thrombosis Risk

20210 G>A G/G

Date Reported: 5/4/2012

2. These are the Raw Data. Each table under the corresponding assay shows all mutaJons tested in the top row and the result in the bobom row. All genes are reported as Normal except those for which a mutaJon is detected. SomeJmes abbreviaJons are used. Het denotes a heterozygous gene mutaJon and Mut denotes a homozygous mutaJon. All of these data are summarized in the result secJon (refer to 1 above).

Assay: MTHFR

Genotype: 667:C/C, 1298:A/C

677 C>T C/C

Phenotype: Normal Thrombosis and Cardiovascular Disease Risk

1298 A>C A/C

Date Reported: 5/4/2012

Natural Molecular Testing Corp 223 SW 41st Street, Renton, Washington 98057, 1-888-442-8881 CLIA Certified DNA Testing Lab Since 2009 Credential Number MTSC.FS.60063043, CLIA #50D1092274

Abbreviations: Het = Heterozygote; Mut = Mutant

3
Page 1 of 2

Genetic Test Results

Patient Name: Robert Simone

Date of Birth: 10/11/1963

NMTC Laboratory #: 15875

TEST INTERPRETATIONS
CYP2C19 - NORMAL METABOLIZER
The subject is a normal metabolizer (NM). NM genotypes consist of two active CYP2C19 alleles. CYP2C19 NMs are the common phenotype for CYP2C19 enzyme activity. In general, they can be administered CYP2C19 metabolized drugs following standard dosing practices. Consult label for dosing guidance.

InterpretaJve Guide to the MulJ-Test GeneJc Report (Page 2)

CYP2C9 - NORMAL METABOLIZER

CYP2C9 - The subject is a normal metabolizer (NM). Extensive (normal) CYP2C9 metabolism is anticipated. NM genotypes consist of two active CYP2C9 alleles. CYP2C9 NMs are the common phenotype for CYP2C9 enzyme activity. In general, normal metabolizers can be administered CYP2C9 metabolized drugs following standard dosing p ractices. Consult label for dosing guidance.

VKORC1 - INTERMEDIATE WARFARIN SENSITIVITY

VKORC1 - Based on VKORC1 genotyping, intermediate warfarin sensitivity is anticipated. I ntermediate s ensitivity V KORC1 h aplotypes c onsist o f o ne m utated a llele i n the VKORC1 gene. A lower dose is recommended for intermediate sensitivity VKORC1 haplotypes.

CYP2D6 - NORMAL METABOLIZER

The test subject is a normal metabolizer (NM). NM genotypes consist of two active CYP2D6 alleles. CYP2D6 NMs have normal levels of enzyme activity. Normal metabolizer genotypes can b e a dministered C YP2D6-m etabolized d rugs s tandard d osing p ractices. Dosing should be considered in the context of other drugs, which may convey an inhibitory effect on the CYP2D6 gene product. Consult label for dosing guidance.

CYP3A4 - NORMAL METABOLIZER

The test subject is a CYP450 3A4 normal metabolizer (NM). NM genotypes consist of two active CYP450 3A4 alleles. CYP450 3A4 NMs are the common phenotype for 3A4 and have normal levels of enzyme activity. In general, they can be administered CYP450 3A4 metabolized drugs following standard dosing practices. Dosing should be considered in the context of other drugs, which may convey an inhibitory effect on the CYP450 3A4 gene product. Consult label for dosing guidance.

CYP3A5 - POOR METABOLIZER

The test subject is a CYP450 3A5 poor metabolizer (PM). PM genotypes consist of two inactive CYP450 3A5 alleles. CYP450 3A5 poor metabolizers have significantly lower levels of enzyme activity. For pro-drugs requiring activation by CYP450 3A5, PMs may require alternative treatment or increased dosage. For other drug types (inactivated b y C YP450 3A5) a cting d irectly o n their targets, PMs may require a lternative treatments o r l ess than s tandard d osage to p revent o verdose toxicity a nd drug interactions. Dosing should be considered in the context of other drugs, which may convey an inhibitory effect on the CYP450 3A5 gene product. Consult label for dosing guidance.

FACTOR II PROTHROMBIN - NORMAL THROMBOSIS RISK

The test subject is wildtype for Factor II Prothrombin. Wildtype genotypes consist of two G residues at the 20210 position of the Factor II gene. Wildtype genotypes are associated w ith a n ormal r isk o f d eveloping a n a bnormal b lood c lot.

3. These are the Lab Test InterpretaEons. Each secJon gives a narraJve explaining what the test result (shown on page 1 of the report) means. Each interpretaJon explains what consJtutes both the genotype and phenotype for the test result. The interpretaJon also includes a brief explanaJon of how paJent treatment may be aected by the geneJc test results.

FACTOR V LEIDEN - NORMAL THROMBOSIS RISK

The test subject is wildtype for Factor V Leiden. Wildtype genotypes consist of two G residues at the 1691 position of the Factor V gene. Wildtype genotypes are associated w ith a n ormal r isk o f d eveloping a n a bnormal b lood c lot.

MTHFR - NORMAL THROMBOSIS AND CARDIOVASCULAR DISEASE RISK

The test subject is wildtype for the 677C>T MTHFR mutation and a heterozygote for the 1298A>C MTHFR mutation. Individual heterozygosity for the 677C>T or the1298A>C MTHFR mutation genotypes does not increase the risk for premature cardiovascular disease or of developing an abnormal blood clot.

ASSAY INFORMATION
Co-administration of other drugs. Genotype results should be interpreted in context of the individual clinical situation including co-administration of other drugs, hepatic and renal function. In all cases monitor for co-administration of inhibitors which may convert patients to poor metabolizer status. Potential adverse outcomes included overdose toxicity or treatment failure particularly for prodrugs. Clinical Indication for Testing: Patients taking medicines metabolized by the cytochrome P450s with a personal or family history of adverse reactions including treatment failure, to confirm the presence or absence of relevant genotypes and as an aid to dosing and co-medication administration. DNA testing does not replace the need for clinical and therapeutic drug monitoring. Methodologies: PCR based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%. CYP2C19: 10 variants (active *1; inactive *2, *3, *4, *6, *7, *8, *9, *10; rapid *17). CYP2D6: 15 variants (active *1, *2; inactive *3, *4, *5, *6, *7, *8, *12, *14; partially active *9, *10, *17, *29, *41; gene duplications XN; gene deletion XN). CYP2C9: 3 variants (active *1, inactive *2, *3). VKORC1: 1 variant (-1639G>A). Rare variants of CYP2D6 (*7, *8, *12, *14) may not have been observed at NMTC. These assays have been developed and performance characteristics determined by NMTC. Rare false negative or false positive results may occur. CYP2C19 and CYP2D6 have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance is not necessary. These tests are used for clinical purposes and should not be considered as investigational. CYP450-3A4: 6 variants (active *1, *1B, *3; inactive *2, *12, *17). CYP450-3A5: 8 variants (active *1, *1D, *2, *7; inactive *3, *3B, *6, *8, *9). variants of CYP450-3A4 and 3A5 may not have been observed at NMTC. These assays have been developed and performance characteristics determined by NMTC. Rare false negative or false positive results may occur. CYP2C19 and CYP2D6 have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance is not necessary. These tests are used for clinical purposes and should not be considered as investigational. Factor V Leiden: 1 variant (1691G>A). Factor II Prothrombin: 1 variant (20210G>A). MTHFR: 2 variants (677C>T and 1298A>C). false negative or false positive results may occur. Each test in this assay has been cleared by the FDA for in vitro diagnostic use.

4. This is GENERAL TEST INFORMATION. It gives a brief summary of clinical signicance and test methodologies. In general, this is non-essenJal informaJon for clinicians but required by CLIA to be reported with the test report.

Natural Molecular Testing Corp 223 SW 41st Street, Renton, Washington 98057, 1-888-442-8881 CLIA Certified DNA Testing Lab Since 2009 Credential Number MTSC.FS.60063043, CLIA #50D1092274

Page 2 of 2

DNA DRUG SENSITIVITY TEST (DST) RESULTS Cytochrome P450 Tests

InterpretaJve Guide to CYP450-2C9 & VKORC1 Single Report

1. These are the test results. The top line shows both the genotype (*1/*1) and phenotype (Normal Metabolizer) for the 2C9 gene. The bobom line shows both the genotype (G/G) and phenotype (Low Warfarin SensiJvity) for the VKORC1 gene. For drug sensiJvity geneJc tesJng, the phenotype tells you how well the paJent will metabolize drugs for the pathway being tested. 2. These are the Lab Test InterpretaEons. These give a narraJve explaining what the test results (shown in 1 above) mean. It explains what consJtutes both the genotype and phenotype for the test result. 3. These are the Raw Data. It shows all mutaJons tested in the leh column and the result in the right column. All genes are reported as Normal except those for which a mutaJon was detected. For the VKORC1 gene a result of Low SensiJvity (G/G) is the normal result. Het means the gene mutaJon is a heterozygote and Mut means the gene mutaJon is homozygous mutaJon. All of these data are summarized in the result secJon (refer to 1 above) 4. This is GENERAL TEST INFORMATION. It gives a brief summary of clinical signicance and test methodologies. In general, this is non-essenJal informaJon for clinicians but required by CLIA to be reported with the test report.

Patient Name: Don Smith Referrer: Dr. Vasquez, MD Date Collected: 05/19/2011

Date of Birth: 6/14/1928 Client Account: Date Received: 05/23/2011

NMTC Laboratory # 384 Sample Type: Buccal Swab Date Reported: June 5, 2011

Cytochrome P450 Test Result(s): Cytochrome Genotype & Phenotype

DST-CYP2C9 *1/*1 Normal Warfarin Metabolizer DST-VKORC1 Low Warfarin Sensitivity (G/G)

Laboratory Director: Vincent Aoki, Ph.D., HCLD (ABB) Natural Molecular Testing Corp.

Laboratory Test Interpretation:

CYP2C9 - The subject is a normal metabolizer. Extensive (normal) warfarin metabolism is anticipated. Normal metabolizer genotypes consist of two active CYP2C9 alleles. CYP2C9 Normal metabolizers are the common phenotype for CYP2C9 enzyme activity. In general, normal metabolizers can be administered CYP2C9 metabolized drugs following standard dosing practices. Consult label for dosing guidance. VKORC1 - Based on VKORC1 genotyping, low warfarin sensitivity is anticipated. Low sensitivity VKORC1 haplotypes consist of two wildtype alleles in the VKORC1 gene.

Raw Data CYP4502C9Allele

*2 *3

Result
Normal Normal LowSensitivity(G/G) PASS PASS

VKORC1 NEG control POS control

Co-administration of other drugs: Genotype results should be interpreted in context of the individual clinical situation including coadministration of other drugs, hepatic and renal function. In all cases monitor for co-administration of inhibitors which may convert patients to poor metabolizer status. Potential adverse outcomes included overdose toxicity or treatment failure particularly for prodrugs.
Clinical Indication for Testing: Patients taking medicines metabolized by the cytochrome P450s with a personal or family history of adverse reactions including treatment failure, to confirm the presence or absence of relevant genotypes and as an aid to dosing and co-medication administration. DNA testing does not replace the need for clinical and therapeutic drug monitoring. Methodologies: PCR based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%. CYP2C19: 10 variants (active *1; inactive *2, *3, *4, *6, *7, *8, *9, *10; rapid *17). CYP2D6: 15 variants (active *1, *2; inactive *3, *4, *5, *6, *7, *8, *12, *14; partially active *9, *10, *17, *29, *41; gene duplications XN; gene deletion XN). CYP2C9: 3 variants (active *1, inactive *2, *3). VKORC1: 1 variant (-1639G>A). Rare variants of CYP2D6 (*7, *8, *12, *14) may not have been observed at NMTC. These assays have been developed and performance characteristics determined by NMTC. Rare false negative or false positive results may occur. CYP2C19 and CYP2D6 have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance is not necessary. These tests are used for clinical purposes and should not be considered as investigational.

Illustrative Guide to Cytochrome P450 Genes: Prevalence and Substrates

CYP2C19 CYP2D6 CYP2C9 10% of drugs including clopidogrel (Plavix), 25% of drugs, including most SSRIs, TCAs, 16% of drugs including most angiotensin II amitriptyline, citalopram, clomipramine, beta blockers, opiates, antihistamines, cough blockers, NSAIDs, hypoglycemics, warfarin diazepam, escitalopram, imipramine, sertraline, medicines, neuroleptics, antiarrhythmics, (Coumadin), sulfonylureas, ibuprofen, some phenytoin, lansoprazole, omeprazole, tamoxifen, carveodilol, metoprolol, propranolol, antidepressants, Amaryl, isoniazid, Hyzaar, carisoprodol, propanolol, and voriconazole. timolol, codeine, and hydrocodone. amitriptyline, Dilantin, naproxen, and Viagra. ~30% typical U.S., higher in Asians and ~50%, increased prevalence in Africans ~35% Africans For more complete information: www.naturalmolecular.com. 1-888-442-8881

Medicines Affected Patients w/Variants

For more detailed information visit our website at www.naturalmolecular.com

Natural Molecular Testing Corp 223 SW 41st Street, Renton, Washington 98057, 1-888-442-8881

Accredited DNA Testing Lab Since 2009

DNA DRUG SENSITIVITY TEST (DST) RESULTS Cytochrome P450 Tests

Patient Name: Patricia Kingsberry Referrer: Dr. Franklin Wefald Date Collected: 3/13/2012

Date of Birth: 9/15/1940 Client Account: 213 Date Received: 3/20/2012

NMTC Laboratory # 11314- 17 Sample Type: Buccal Swab Date Reported: 3/22/2012

InterpretaJve Guide to CYP450-2C19 Single Report

1. This is the test result. It shows both the genotype (*1/*17) and phenotype (Rapid Metabolizer). For drug sensiJvity geneJc tesJng, the phenotype tells you how well the paJent will metabolize drugs for the pathway being tested. 2. This is the Lab Test InterpretaEon. It gives a narraJve explaining what the test result (shown in 1 above) means. It explains what consJtutes both the genotype and phenotype for the test result. 3. This is the Raw Data. It shows all mutaJons tested in the leh column and the result in the right column. All genes are reported as Normal except those for which a mutaJon was detected (17-Het in this example). Het means the gene mutaJon is a heterozygote and Mut means the gene mutaJon is homozygous mutaJon. All of these data are summarized in the result secJon (refer to 1 above)

Cytochrome P450 Test Result(s): Cytochrome Genotype Phenotype Interpretation:

DST-CYP2C19 *1/*17 Rapid Metabolizer

Laboratory Director: Vincent Aoki, Ph.D., HCLD (ABB) Natural Molecular Testing Corp.

Laboratory Test Interpretive Comments:

The test subject is a rapid metabolizer (rapid activator of clopidogrel). Rapid metabolizer genotypes consist of one increased and one normal activity CYP2C19 mutatedAlleles. CYP2C19 Rapid Metabolizers have elevated levels of enzyme activity. For pro-drugs, like clopidogrel, rapid metabolizers readily convert the drug into its active metabolite. Thus, rapid metabolizers may be at increased risk of elevated exposure to the active drug metabolites and may require lower than standard dosage of pro-drug. For other drug types (inactivated by CYP2C19) acting directly on their targets rapid metabolizers may require more than standard dosage to prevent treatment failure. Clopidogrel (Plavix): Bleeding risk increased. Consult label for dosing guidance. Raw Data

CYP450'2C19'Allele' *2# *3# *4# *5# *6# *7# *8# *9# *10# *13# *17#

Result' Normal# Normal# Normal# Normal# Normal# Normal# Normal# Normal# Normal# Normal# *173Het#

Co-administration of other drugs. Genotype results should be interpreted in context of the individual clinical situation including coadministration of other drugs, hepatic and renal function. In all cases monitor for co-administration of inhibitors which may convert patients to poor metabolizer status. Potential adverse outcomes included overdose toxicity or treatment failure particularly for prodrugs.
Clinical Indication for Testing: Patients taking medicines metabolized by the cytochrome P450s with a personal or family history of adverse reactions including treatment failure, to confirm the presence or absence of relevant genotypes and as an aid to dosing and co-medication administration. DNA testing does not replace the need for clinical and therapeutic drug monitoring. Methodologies: PCR based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%. CYP2C19: 8 variants (active *1; inactive *2, *3, *4, *5, *6, *7, *8; rapid *17). CYP2D6: 17 variants (active *1, *2; inactive *3,*4, *5, *6, *7, *11, *12, *14, *15; partially active *9, *10, *17, *41; gene duplications *1, *2, *4, *10, *41). CYP2C9: 5 variants (active *1, Inactive *2, *3, *4, *5, *6). VKORC1: 1 variant (-1639G>A). Rare variants of CYP2D6 (*7, *8, *11, *12, *14, *15) and CYP2C9 (*4) may not have been observed at NMTC. Assays developed and performance characteristics determined by NMTC. Rare false negative or false positive results may occur.

Illustrative Guide to Cytochrome P450 Genes: Prevalence and Substrates

CYP2C19 CYP2D6 CYP2C9 10% of drugs including clopidogrel (Plavix), 25% of drugs, including most SSRIs, TCAs, 16% of drugs including most angiotensin II amitriptyline, citalopram, clomipramine, beta blockers, opiates, antihistamines, cough blockers, NSAIDs, hypoglycemics, warfarin diazepam, escitalopram, imipramine, sertraline, medicines, neuroleptics, antiarrhythmics, (Coumadin), sulfonylureas, ibuprofen, some phenytoin, lansoprazole, omeprazole, tamoxifen, carveodilol, metoprolol, propranolol, antidepressants, Amaryl, isoniazid, Hyzaar, carisoprodol, propanolol, and voriconazole. timolol, codeine, and hydrocodone. amitriptyline, Dilantin, naproxen, and Viagra. ~30% typical U.S., higher in Asians and ~50%, increased prevalence in Africans ~35% Africans For more complete information: www.naturalmolecular.com. 1-888-442-8881 Natural Molecular Testing Corporation Credential Number#: MTSC.FS.60063043, CLIA No. 50D1092274 .

Medicines Affected Patients w/Variants

4. This is GENERAL TEST INFORMATION. It gives a brief summary of clinical signicance and test methodologies. In general, this is non-essenJal informaJon for clinicians but required by CLIA to be reported with the test report.

For more detailed information visit our website at www.naturalmolecular.com

Natural Molecular Testing Corp ! 223 SW 41st Street, Renton, Washington 98057, 1-888-442-8881

Accredited DNA Testing Lab Since 2009

DNA DRUG SENSITIVITY TEST (DST) RESULTS Cytochrome P450 Tests

InterpretaJve Guide to CYP450-2D6 Single Report

1. This is the test result. It shows both the genotype (*1/*41) and phenotype (Intermediate Metabolizer). For drug sensiJvity geneJc tesJng, the phenotype tells you how well the paJent will metabolize drugs for the pathway being tested. 2. This is the Lab Test InterpretaEon. It gives a narraJve explaining what the test result (shown in 1 above) means. It explains what consJtutes both the genotype and phenotype for the test result. 3. These are the Raw Data. It shows all mutaJons tested in the leh column and the result in the right column. All genes are reported as Normal except those for which a mutaJon was detected (41-Het in this example). Het means the gene mutaJon is a heterozygote and Mut means the gene mutaJon is homozygous mutaJon. All of these data are summarized in the result secJon (refer to 1 above)

Patient Name: Donald Ellison Referrer: Dr. Vasquez Date Collected: 5/16/2011

Date of Birth: 04/06/1954 Client Account: Date Received: 5/18/2011

NMTC Laboratory # 348 Sample Type: Buccal Swab Date Reported: June 2, 2011

Cytochrome P450 Test Result(s): Cytochrome Genotype & Phenotype

DST-CYP2D6 *1/*41 Intermediate Metabolizer

Laboratory Director: Vincent Aoki, Ph.D., HCLD (ABB) Natural Molecular Testing Corp.

Laboratory Test Interpretation:

The test subject is an intermediate metabolizer. Intermediate metabolizer genotypes consist of one active CYP2D6 allele and one inactive CYP2D6 allele. CYP2D6 Intermediate Metabolizers have lower levels of enzyme activity (approximately half of the activity versus a normal metabolizer). For pro-drugs requiring activation by CYP2C19, intermediate metabolizers do not convert the drug into its active metabolite as efficiently as normal metabolizers. Thus, intermediate metabolizers may require alternative treatment or increased dosage of pro-drug. For other drug types (inactivated by CYP2C19) acting directly on their targets, intermediate metabolizers may require alternative treatments or less than standard dosage to prevent overdose toxicity and drug interactions. Dosing should be considered in the context of other drugs, which may convey an inhibitory effect on the CYP2D6 gene product. Consult label for dosing guidance.

Raw Data CYP4502D6Allele Result

*2 Normal *3 Normal *4 Normal *6 Normal *8/*14 Normal *9 Normal *10 Normal *12 Normal *17 Normal *29 Normal 1584C>G Normal *41 *41Het *CNV Normal *5(XN) Normal Co-administration of other drugs. Genotype results should be interpreted in context of the individual clinical situation including coadministration of other drugs, hepatic and renal function. In all cases monitor for co-administration of inhibitors which may convert patients to poor metabolizer status. Potential adverse outcomes included overdose toxicity or treatment failure particularly for prodrugs.
Clinical Indication for Testing: Patients taking medicines metabolized by the cytochrome P450s with a personal or family history of adverse reactions including treatment failure, to confirm the presence or absence of relevant genotypes and as an aid to dosing and co-medication administration. DNA testing does not replace the need for clinical and therapeutic drug monitoring. Methodologies: PCR based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%. CYP2C19: 10 variants (active *1; inactive *2, *3, *4, *6, *7, *8, *9, *10; rapid *17). CYP2D6: 15 variants (active *1, *2; inactive *3, *4, *5, *6, *7, *8, *12, *14; partially active *9, *10, *17, *29, *41; gene duplications XN; gene deletion XN). CYP2C9: 3 variants (active *1, inactive *2, *3). VKORC1: 1 variant (-1639G>A). Rare variants of CYP2D6 (*7, *8, *12, *14) may not have been observed at NMTC. These assays have been developed and performance characteristics determined by NMTC. Rare false negative or false positive results may occur. CYP2C19 and CYP2D6 have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance is not necessary. These tests are used for clinical purposes and should not be considered as investigational.

Illustrative Guide to Cytochrome P450 Genes: Prevalence and Substrates

CYP2C19 10% of drugs including clopidogrel (Plavix), amitriptyline, citalopram, clomipramine, diazepam, escitalopram, imipramine, sertraline, phenytoin, lansoprazole, omeprazole, carisoprodol, propanolol, and voriconazole. ~30% typical U.S., higher in Asians and Africans CYP2D6 25% of drugs, including most SSRIs, TCAs, beta blockers, opiates, antihistamines, cough medicines, neuroleptics, antiarrhythmics, tamoxifen, carveodilol, metoprolol, propranolol, timolol, codeine, and hydrocodone. ~50%, increased prevalence in Africans CYP2C9 16% of drugs including most angiotensin II blockers, NSAIDs, hypoglycemics, warfarin (Coumadin), sulfonylureas, ibuprofen, some antidepressants, Amaryl, isoniazid, Hyzaar, amitriptyline, Dilantin, naproxen, and Viagra. ~35%

Medicines Affected Patients w/Variants

4. This is GENERAL TEST INFORMATION. It gives a brief summary of clinical signicance and test methodologies. In general, this is non-essenJal informaJon for clinicians but required by CLIA to be reported with the test report.

For more complete information: www.naturalmolecular.com. 1-888-442-8881 Natural Molecular Testing Corporation Credential Number#: MTSC.FS.60063043, CLIA No. 50D1092274.

For more detailed information visit our website at www.naturalmolecular.com

Natural Molecular Testing Corp 223 SW 41st Street, Renton, Washington 98057, 1-888-442-8881

Accredited DNA Testing Lab Since 2009

DNA DRUG SENSITIVITY TEST (DST) RESULTS Cytochrome P450 Tests

InterpretaJve Guide to the CYP450-3A4&3A5 Single Report

1. These are the test results. The top line contains the 3A4 genotype (*1/*1B) and phenotype (NormalMetabolizer). The bobom line contains the 3A5 genotype (*1/*6) and phenotype (Intermediate Metabolizer). For drug sensiJvity geneJc tesJng, the phenotype tells you how well the paJent will metabolize drugs for the pathway being tested. 2. These are the Lab Test InterpretaEons. This secJon gives a narraJve explaining what the test results (shown in 1 above) mean. These secJons explain what consJtute both the genotypes and phenotypes for the test results. 3. These are the Raw Data. The data tables show all mutaJons tested in the leh columns and the results in the right columns. All genes are reported as Normal except those for which a mutaJon was detected (*1B-Heterozygote and*6- Heterozygote) in this example). All of these data are summarized in the result secJon (refer to 1 above)

Patient Name: Thomas Guillory Referrer: Dr. Brian Le Date Collected: 11/14/2011

Date of Birth: 5/20/1960 Sample Type: Buccal Swab Date Received: 11/15/2011

NMTC Laboratory #: 4041-21,22 Date Reported: 11/22/2011

DRUG SENSITIVITY TEST RESULTS

ASSAY CYP450- 3A4 CYP450- 3A5

GENOTYPE *1/*1B *1/*6

PHENOTYPE Normal Metabolizer Intermediate Metabolizer

Laboratory Director: Vincent Aoki, Ph.D., HCLD (ABB) Natural Molecular Testing Corp.

Laboratory Test Interpretation(s): CYP450-3A4 Normal Metabolizer!

The test subject is a normal CYP450 3A4 metabolizer. Normal metabolizer genotypes consist of two active CYP450 3A4 alleles. CYP450 3A4 Normal Metabolizers are the common phenotype for 3A4 and have normal levels of enzyme activity. In general, they can be administered CYP450 3A4 metabolized drugs following standard dosing practices. Dosing should be considered in the context of other drugs, which may convey an inhibitory effect on the CYP450 3A4 gene product. Consult label for dosing guidance.

CYP450-3A5 Intermediate Metabolizer

The test subject is an intermediate CYP450 3A5 metabolizer. Intermediate metabolizer genotypes consist of one active CYP450 3A5 allele and one inactive CYP450 3A5. CYP450 3A5 Intermediate Metabolizers have lower levels of enzyme activity (approximately half of the activity versus a normal metabolizer). For pro-drugs requiring activation by CYP450 3A5, intermediate metabolizers do not convert the drug into its active metabolite as efficiently as normal metabolizers. Thus, intermediate metabolizers may require alternative treatment or increased dosage of pro-drug. For other drug types (inactivated by CYP450 3A5) acting directly on their targets, intermediate metabolizers may require alternative treatments or less than standard dosage to prevent overdose toxicity and drug interactions. Dosing should be considered in the context of other drugs, which may convey an inhibitory effect on the CYP450 3A5 gene product. Consult label for dosing guidance.

Polymorphism/Allele Raw Data

CYP450'3A4' *1B$ *2$ *3$ *12$ *17$ $ $ $ Result' *1B%Heterozygote$ Normal$ Normal$ Normal$ Normal$ $ $ $ CYP450'3A5' *1D$ *2$ *3$ *3B$ *6$ *7$ *8$ *9$ Result' Normal$ Normal$ Normal$ Normal$ *6%Heterozygote$ Normal$ Normal$ Normal$

Co-administration of other drugs: Genotype results should be interpreted in context of the individual clinical situation including co-administration of other drugs, hepatic and renal function. In all cases monitor for co-administration of inhibitors, which may convert patients to poor metabolizer status. Potential adverse outcomes include overdose toxicity or treatment failure particularly for prodrugs. Clinical Indication for Testing: Patients taking medicines metabolized by the cytochrome P450s with a personal or family history of adverse reactions including treatment failure, to confirm the presence or absence of relevant genotypes and as an aid to dosing and co-medication administration. DNA testing does not replace the need for clinical and therapeutic drug monitoring. Methodologies: PCR based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%. CYP450-3A4: 6 variants (active *1, *1B, *3; inactive *2, *12, *17). CYP450-3A5: 8 variants (active *1, *1D, *2, *7; inactive *3, *3B, *6, *8, *9). Rare variants of CYP450-3A4 and 3A5 may not have been observed at NMTC. These assays have been developed and performance characteristics determined by NMTC. Rare false negative or false positive results may occur. CYP2C19 and CYP2D6 have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance is not necessary. These tests are used for clinical purposes and should not be considered as investigational.

Illustrative Guide to Cytochrome P450 Genes: Prevalence and Substrates

CYP450 3A4 & 3A5 Medicines Affected Patients w/ Variants 50% of all marketed medications including: tamoxifen, clopidogrel (Plavix), atorvastin, esomeprazole, escitalopram, lansoprazole, fluticasone, venlafaxine, tamsulosin, celecoxib, alprazolam, azithromycin, carbamezapine, Diazepam. Inhibitors of 3A4: Goldenseal and Grapefruit. Inhibitors of 3A5: Goldenseal. Inducers of 3A4: St. Johns Wort ~5-10% Caucasions, 5-8% African Americans, 1-3% Asians
For more complete information: www.naturalmolecular.com. 1-888-442-8881

4. This is GENERAL TEST INFORMATION. It gives a brief summary of clinical signicance and test methodologies. In general, this is non-essenJal informaJon for clinicians but required by CLIA to be reported with the test report.

Natural Molecular Testing Corporation Credential Number#: MTSC.FS.60063043, CLIA No. 50D1092274 .

For more detailed information visit our website at www.naturalmolecular.com

Natural Molecular Testing Corp ! 223 SW 41st Street, Renton, Washington 98057, 1-888-442-8881

Accredited DNA Testing Lab Since 2009

THROMBOPHILIA RISK TEST RESULTS

InterpretaJve Guide to the Thrombosis Risk Test Single Report

1. These are the test results. The top line shows both the genotype (G/G) and phenotype (Normal Thrombosis Risk) for the Factor V Leiden gene. The middle line shows both the genotype (G/G) and phenotype (Normal Thrombosis Risk) for the Factor II Prothrombin gene. The bobom two lines show both the genotypes (677 T/T & 1298 A/A) and phenotype (Signicant Thrombosis and Cardiovascular Disease Risk) for the two MTHFR genes. 2. These are the Lab Test InterpretaEons. Each gives a narraJve explaining what the test results (shown in 1 above) mean. It explains what consJtutes both the genotype and phenotype for eachtest result. 3. These are the Raw Data. The table shows all mutaJons tested in the leh columns and the results in the right columns. All genes are reported as Normal except those for which a mutaJon was detected (Mutant (T/T) in this example). All of these data are summarized in the result secJon (refer to 1 above) 4. This is GENERAL TEST INFORMATION. It gives a brief summary of clinical signicance and test methodologies. In general, this is non-essenJal informaJon for clinicians but required by CLIA to be reported with the test report.

Patient Name: Ralph Villarreal Referrer: Dr. Bruce Bowers Date Collected: 10/10/2011

Date of Birth: 11/2/1950 Sample Type: Buccal Swab Date Received: 10/14/2011

NMTC Laboratory # 3369 - 10

Date Reported: 10/31/2011

THROMBOPHILIA RISK TEST RESULTS

ASSAY FACTOR V LEIDEN FACTOR II PROTHROMBIN MTHFR

GENOTYPE 1691 G/G 20210 G/G 677 T/T 1298 A/A

PHENOTYPE Normal Thrombosis Risk Normal Thrombosis Risk Significant Thrombosis and Cardiovascular Disease Risk

Laboratory Director: Vincent Aoki, Ph.D., HCLD (ABB) Natural Molecular Testing Corp.

Laboratory Test Interpretation(s): (See below for raw data)

FACTOR V LEIDEN - NORMAL THROMBOSIS RISK Factor V Leiden The test subject is wildtype for Factor V Leiden. Wildtype genotypes consist of two G residues at the 1691 position of the Factor V gene. Wildtype genotypes are associated with a normal risk of developing an abnormal blood clot. FACTOR II PROTHROMBIN NORMAL THROMBOSIS RISK Factor II Prothrombin - The test subject is wildtype for Factor II Prothrombin. Wildtype genotypes consist of two G residues at the 20210 position of the Factor II gene. Wildtype genotypes are associated with a normal risk of developing an abnormal blood clot. MTHFR SIGNIFICANT THROMBOSIS AND CARDIOVASCULAR DISEASE RISK MTHFR The test subject is a homozygous mutant for the 677C>T MTHFR mutation and wildtype for the 1298A>C MTHFR mutation. Homozygosity for the of 677C>T MTHFR mutation is associated with increased plasma homocysteine and a threefold increase in premature cardiovascular disease.

Polymorphism/Allele Raw Data

Factor'V' Leiden' 1691$G>A$ $ ' Result' Normal$(G/G)$ $ Factor'II' Prothrombin' 20210$G>A$ $ ' Result' Normal$(G/G)$ $ '
MTHFR'

677$C>T$ 1298$A>C$

' Result' Mutant$(T/T)$ Normal$(A/A)$

Clotting Risk and Other Genes: Genotype results should be interpreted in context of the individual clinical situation including administration of drugs and other individual clinical characteristics. The Factor V Leiden, Prothrombin (Factor II), and MTHFR mutations represent a few of a growing panel of hereditary thrombophilia risk factors. The risk of thromboembolism in individuals with more than one genetic risk factor is synergistic and should be considered severe. Therefore, evaluation for the presence of coexisting genetic abnormalities should be considered. Clinical Indication for Testing: Patients with a history of thromboembolism, coronary artery disease, and/or stroke, history of pregnancy complications including recurrent pregnancy loss, relatives of individuals with history of events and gene mutations. Methodologies: PCR based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%. Factor V Leiden: 1 variant (1691G>A). Factor II Prothrombin: 1 variant (20210G>A). MTHFR: 2 variants (677C>T and 1298A>C). Rare false negative or false positive results may occur. Each test in this assay has been cleared by the FDA for in vitro diagnostic use.

Illustrative Guide to Thrombophilia Risk Genes: Prevalence and Substrates

FACTOR V LEIDEN
Risks Associated with Mutations & Population Incidence Thrombosis Risks Wildtype general population: 1 in 1000 Heterozygotes: 4-8-fold increase (1 in 100-125) Homozygote Mutants: 80-fold increase (1 in 12) Incidence ~5% in Caucasians, less common in Hispanics & African Americans, extremely rare in Asians.

FACTOR II PROTHROMBIN

MTHFR

Thrombosis Risks C667T: 5-10% in Caucasians Wildtype general population: 1 in 1000 A1298C: 30% in the General Population Heterozygotes: 3-5 fold increase 11% in Venous thromboembolism cases Homozygote Mutants: 15-fold increase 19% in artery disease cases Incidence Each 5 mol/L increase in total homocysteine levels ~3% in Healthy Individuals (primarily whites) = a 60% increase (men) and a 80% increase (women) 18% in known familial cases of coronary artery disease 6-8% in Venous thrombosis cases 3-5% in Arterial thrombosis cases Natural Molecular Testing Corporation Credential Number#: MTSC.FS.60063043, CLIA No. 50D1092274 .

For more detailed information visit our website at www.naturalmolecular.com

Natural Molecular Testing Corp ! 223 SW 41st Street, Renton, Washington 98057, 1-888-442-8881

Accredited DNA Testing Lab Since 2009

CYP2C9 GENOTYPING INTERPRETATION SUMMARY CYP2C9 PHENOTYPE Normal Metabolizer Intermediate Metabolizer Poor Metabolizer VKOCR1 PHENOTYPE Low Sensitivity Intermediate Sensitivity High Sensitivity

! ! ! ! ! ! ! ! ! !

INTERPRETATION/RECOMMENDATION Subject is a normal metabolizer of warfarin. Normal warfarin metabolizer genotypes consist of two active function CYP2C9 alleles. Refer to Table 1 below for dosing guidance. Subject is an intermediate metabolizer of warfarin. Intermediate warfarin metabolizer genotypes consist of one active function CYP2C9 allele and one reduced function CYP2C9 allele (Increased caution should be observed with *3 variants). Refer to Table 1 below for dosing guidance. Subject is a poor metabolizer of warfarin. Subject will not effectively metabolize warfarin. Poor warfarin metabolizer genotypes consist of two reduced function CYP2C9 alleles. Particular caution should be observed with *3 variants. Refer to Table 1 below for dosing guidance. INTERPRETATION/RECOMMENDATION Subject is expected to experience low sensitivity to warfarin. Refer to Table 1 below for dosing guidance. Subject is expected to experience intermediate sensitivity to warfarin. Refer to Table 1 below for dosing guidance. Subject is expected to experience high sensitivity to warfarin. Refer to Table 1 below for dosing guidance.

GENOTYPE(S) *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3

GENOTYPE(S) G/G G/A A/A

! ! ! ! ! !

Avoid using warfarin with CYP2C9 inhibitors. Patient care and other standard therapies are always the judgment of the managing physician Specific pharmacological questions should be directed to a qualified pharmacogeneticist or Pharm-D.

Table 1: Range of Expected Therapeutic Warfarin Doses Based on CYP2C9 and VKORC1 Genotypes CYP2C9 VKOCR1 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg G/G 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg G/A 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg A/A
Table is taken directly from the warfarin package insert. Ranges are derived from multiple published clinical studies. Other clinical factors (eg, age, race, body weight, sex, concomitant medications, and comorbidities) are generally accounted for along with genotype in the ranges expressed in the table. VKORC1 1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen.

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CYP2C19 GENOTYPING INTERPRETATION SUMMARY PHENOTYPE Normal Metabolizer INTERPRETATION/RECOMMENDATION ! Subject is a normal metabolizer (normal activator) of clopidogrel. ! Subject will convert clopidogrel into its active metabolite at a normal rate. ! Clopidogrel dosage should be standard (300 mg loading dose continued with 75 mg daily maintenance dose). ! Subject is a normal-intermediate metabolizer (normal-intermediate activator) of clopidogrel. ! Subject will convert clopidogrel to its active metabolite at a slightly lower efficiency than normal metabolizers. ! Clopidogrel dosage should start at standard levels but consider using a platelet function assessment to monitor the drugs effects. If the effect of daily maintenance dose is not sufficient, consider using a larger daily maintenance does (150 mg). ! Subject is an intermediate metabolizer (intermediate activator) of clopidogrel. ! Subject will convert clopidogrel to its active metabolite but at a lower efficiency. ! Clopidogrel dosage should start at standard levels but consider using a platelet function assessment to monitor the drugs effects. If the effect of daily maintenance dose is not sufficient, consider using a larger daily maintenance does (150 mg). ! Subject is a poor metabolizer (poor activator) of clopidogrel. ! Subject will not effectively convert clopidogrel to its active metabolite. ! Consider starting clopidogrel at 600 mg (loading dose) with a 150 mg daily maintenance dose. ! Pharmacological effects of clopidogrel should be monitored closely. ! Other drugs should be considered in lieu of clopidogrel. ! Other genotypes include combinations of heterozygotes (i.e. *2/*3, *2/*4, *2/*5, etc.) ! Subject is a rapid metabolizer (rapid activator) of clopidogrel. ! Subject readily converts clopidogrel to its active metabolite. ! Consider starting clopidogrel at 300 mg (loading dose) with a 75 mg daily maintenance dose. Pharmacological effects of the drug should be monitored closely and if necessary consider lowering daily dosage, or consider another drug in lieu of clopidogrel. ! Rapid metabolizers may be at increased bleeding risk. ! Subject is an ultra rapid metabolizer (rapid activator) of clopidogrel. ! Subject readily converts clopidogrel to its active metabolite at very elevated rates. ! Consider starting clopidogrel at lower loading dose and lower daily maintenance dose. Pharmacological effects of the drug should be monitored closely and if necessary consider lowering daily dosage, or consider another drug in lieu of clopidogrel. ! Ultra rapid metabolizers may be at increased bleeding risk. GENOTYPE(S) *1/*1

Normal Intermediate Metabolizer

*2/*17 *3/*17 *4/*17 *6/*17 *1/*2 *1/*3 *1/*4 *1/*6 *2/*2 *3/*3 *4/*4 *6/*6

*7/*17 *8/*17 *9/*17 *10/*17 *1/*7 *1/*8 *1/*9 *1/*10 *7/*7 *8/*8 *9/*9 *10/*10

Intermediate Metabolizer

Poor Metabolizer

Rapid Metabolizer

*1/*17

Ultra-Rapid Metabolizer

*17/17

* Avoid using clopidogrel with omeprazole (a CYP2C19 inhibitor). Patient care and other standard therapies are always the judgment of the managing physician Specific pharmacological questions should be directed to a qualified pharmacogeneticist or Pharm-D.

11

CYP2D6 GENOTYPING INTERPRETATION SUMMARY

PHENOTYPE Normal Metabolizer

INTERPRETATION/RECOMMENDATION ! Subject is a normal metabolizer of 2D6 metabolized drugs ! 2D6 metabolized drug dosage should be standard ! Normal 2D6 metabolizer genotypes consist of two active function CYP2D6 alleles (*1 or *2).

GENOTYPE(S) *1/*1 *1/*2 *2/*2 *1/*3 *1/*4 *1/*5 *1/*6 *1/*8 *1/*9 *1/*10 *1/*12 *1/*14 *1/*17 *1/*29 *1/*41 *3/*3 *4/*4 *5/*5 *6/*6 *8/*8 *9/*9 *2/*3 *2/*4 *2/*5 *2/*6 *2/*8 *2/*9 *2/*10 *2/*12 *2/*14 *2/*17 *2/*29 *2/*41 *10*10 *12/*12 *14/*14 *17/*17 *29/*29 *41/*41

Intermediate Metabolizer

! Subject is an intermediate metabolizer of 2D6 metabolized drugs ! Subject will clear 2D6 metabolized drugs or activate 2D6 metabolized drugs (pro-drugs) to their active metabolites but at a lower efficiency. ! Dosage should start at standard levels but with increased caution ! Intermediate 2D6 metabolizer genotypes consist of one active function (*1 or *2) and one poor function CYP2D6 allele (*3, *4, *6, *5, *8, *9, *10, *12, *14, *17, *29, *41 ).

Poor Metabolizer

! Subject is a poor metabolizer of 2D6 metabolized drugs. ! Subject will not clear 2D6 metabolized drugs nor activate 2D6 metabolized drugs (pro-drugs) to their active metabolites. ! Pharmacological effects of 2D6 metabolized should be monitored closely. ! Alternative drugs should be considered. ! Poor 2D6 metabolizer genotypes consist of two poor function CYP2D6 alleles (*3, *4, *6, *5, *8, *9, *10, *12, *14, *17, *29, *41 ). ! Other genotypes include combinations of heterozygotes (i.e. *3/*4, *4/*5, *3/*10, etc.) ! Subject is a rapid metabolizer of 2D6 metabolized drugs. ! Subject readily clears and converts 2D6 metabolized drugs to their active metabolites. ! Rapid 2D6 metabolizer genotypes consist of two active function alleles (*1 or *2) and a CYP2D6 gene duplication (*XN ).

Rapid Metabolizer

*1/*1 + *XN *1/*2 + *XN *2/*2 + XN

Patient care and other standard therapies are always the judgment of the managing physician Specific pharmacological questions should be directed to a qualified pharmacogeneticist or Pharm-D.

12

CYP3A4&3A5 GENOTYPING INTERPRETATION SUMMARY

3A4 INTERPRETATION GUIDE

PHENOTYPE Normal Metabolizer ! ! ! ! ! ! ! ! ! ! ! ! INTERPRETATION/RECOMMENDATION Subject is a normal metabolizer of 3A4 metabolized drugs 3A4 metabolized drug dosage should be standard Normal 3A4 metabolizer genotypes consist of two active function CYP3A4 alleles (*1, *1B). Subject is an intermediate metabolizer of 3A4 metabolized drugs Subject will clear 3A4 metabolized drugs or activate 3A4 metabolized drugs (pro-drugs) to their active metabolites but at a lower efficiency. Dosage should start at standard levels but with increased caution Intermediate 3A4 metabolizer genotypes consist of one active function (*1 or *1B) and one poor function CYP3A4 allele (*12, *17). Subject is a poor metabolizer of 3A4 metabolized drugs. Subject will not clear 3A4 metabolized drugs nor activate 3A4 metabolized drugs (pro-drugs) to their active metabolites. Pharmacological effects of 3A4 metabolized should be monitored closely. Alternative drugs should be considered. Poor 3A4 metabolizer genotypes consist of two poor function CYP3A4 alleles (*12 or *17 ). GENOTYPE(S) *1/*1 *1/*1B *1B/*1B *1/*12 *1/*17 *1B/*12 *1B/*17 *12/*12 *17/*17 *12/*17

Intermediate Metabolizer

Poor Metabolizer

3A5 INTERPRETATION GUIDE

PHENOTYPE Normal Metabolizer INTERPRETATION/RECOMMENDATION ! Subject is a normal metabolizer of 3A5 metabolized drugs ! 3A5 metabolized drug dosage should be standard ! Normal 3A5 metabolizer genotypes consist of two active function CYP3A5 alleles (*1, *7). ! Subject is an intermediate metabolizer of 3A5 metabolized drugs ! Subject will clear 3A5 metabolized drugs or activate 3A5 metabolized drugs (pro-drugs) to their active metabolites but at a lower efficiency. ! Dosage should start at standard levels but with increased caution ! Intermediate 3A5 metabolizer genotypes consist of one active function (*1 or *7) and one poor function CYP3A5 allele (*3, *3B, *6, *8, *9). ! Subject is a poor metabolizer of 3A5 metabolized drugs. ! Subject will not clear 3A5 metabolized drugs nor activate 3A5 metabolized drugs (pro-drugs) to their active metabolites. ! Pharmacological effects of 3A5 metabolized should be monitored closely. ! Alternative drugs should be considered. ! Poor 3A5 metabolizer genotypes consist of two poor function CYP3A5 alleles (*3, *3B, *6, *8, *9). Other genotypes include combinations of heterozygotes (i.e. *3/*6, *4/*5, *etc.) GENOTYPE(S) *1/*1 *7/*7 *1/*7 *1/*3 *1/*3B *1/*6 *1/*8 *1/*9 *3/*3 *3B/*3B *6/*6 *8/*8 *9/*9

Intermediate Metabolizer

Poor Metabolizer

Patient care and other standard therapies are always the judgment of the managing physician Specific pharmacological questions should be directed to a qualified pharmacogeneticist or Pharm-D.

13

THROMBOSIS RISK TEST GENOTYPING INTERPRETATION SUMMARY

FACTOR V LEIDIN
PHENOTYPE Normal Thrombosis Risk Moderate Thrombosis Risk High Thrombosis Risk INTERPRETATION/RECOMMENDATION ! Subject has a normal genotype for Factor V (1691 G/G) ! Based on Factor V genotype the patient has no increased risk of thrombosis. ! Subject is heterozygous for the Factor V Leiden Mutation (1691 G/A) ! Factor V Leiden heterozygosity is associated with an increased risk (approximately 4 to 8-fold higher than normal genotypes) of developing an abnormal blood clot and may carry as high as a 1 in 100-125 risk of thrombosis (vs. 1 in 1000 in the general population) ! Subject is a homozygous mutant for the Factor V Leiden Mutation (1691 A/A) ! Factor V Leiden homozygosity is associated with a significant risk (approximately 80-fold higher than normal genotypes) of developing an abnormal blood clot and may carry as high as a 1 in 12 risk of thrombosis (vs. 1 in 1000 in the general population) GENOTYPE(S) 1691 G/G

1691 G/A

1691 A/A

FACTOR II PROTHROMBIN
PHENOTYPE Normal Thrombosis Risk Moderate Thrombosis Risk High Thrombosis Risk INTERPRETATION/RECOMMENDATION ! Subject has a normal genotype for Factor II Prothrombin (20210 G/G) ! Based solely on Factor II genotype the patient has no increased risk of thrombosis. ! Subject is heterozygous for the Factor II Prothrombin mutation (20210 G/A) ! Factor II Prothrombin heterozygosity is associated with a moderate risk (approximately 3 to 5-fold higher than normal genotypes) of developing an abnormal blood clot. ! Thrombosis risk increases synergistically in the presence of Factor V Leiden mutations. ! Subject is a homozygous mutant for the Factor II Prothrombin Mutation (20210 A/A) ! Factor II Prothrombin homozygous mutants are rare and carry a significant risk of developing an abnormal blood clot. ! Thrombosis risk increases synergistically in the presence of Factor V Leiden mutations. GENOTYPE(S) 20210 G/G

20210 G/A

20210 A/A

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THROMBOSIS RISK TEST GENOTYPING INTERPRETATION SUMMARY

METHYL TETRAHYDROFOLATE REDUCTASE (MTHFR)

PHENOTYPE Normal Thrombosis & Cardiovascular Disease Risk Moderate Thrombosis & Cardiovascular Disease Risk Significant Thrombosis & Cardiovascular Disease Risk INTERPRETATION/RECOMMENDATION ! Subject either has a normal genotype for both MTHFR mutations (677 C/C and 1298 A/A) or carries individual heterozygosity for one of the MTHFR mutations (677 C/T OR 1298 A/C) ! Wildtype genotypes for the MTHFR gene are associated with normal risk of thrombosis and cardiovascular disease. ! Individual heterozygosity for the 677C>T OR the 1298 A>C MTHFR mutations is not associated with elevated plasma homocysteine levels and does not increase the risk for premature cardiovascular disease or of developing an abnormal blood clot. ! Subject is heterozygous for both MTHFR Mutations (677 C/T AND 1298 A/C). ! Compound heterozygosity (677C/T and 1298A/C) is associated with increased plasma homocysteine levels and may be associated with increased risk of premature cardiovascular disease. GENOTYPE(S) 677 C/C + 1298 A/A 677 C/T + 1298 A/A 677 C/C + 1298 A/C

677 C/T + 1298 A/C

! Subject is a homozygous mutant for the MTHFR 677 C>T Mutation (677 T/T) ! Homozygosity for the of 677C>T MTHFR mutation is associated with increased plasma homocysteine and a threefold increase in premature cardiovascular disease.

677 T/T

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