Laboratory Testing in Clinical Pharmacogenetics: How to Choose … · 2018/11/1 · Matching clinical workflows with laboratory logistics 3. Understanding how results are reported

Precision Medicine ConferencePrecision Medicine Conference

Henry “Mark” Dunnenberger PharmD BCPSDirector – Pharmacogenomics

NorthShore University HealthSystem

Laboratory Testing in Clinical Pharmacogenetics:

How to Choose a Commercial Laboratory

• I declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.

• The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

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Disclosure

• Compare and contrast approaches to clinical laboratory testing in pharmacogenomics.

• Explain practice‐based differences between panel‐based testing as compared with testing individual genes for pharmacogeneticrecommendations.

• List criteria for evaluating commercial pharmacogenetic testing laboratories.

• Identify essential information needed when interpreting commercial laboratory reports in pharmacogenetics.

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Objectives

A. Commercial laboratory – panel‐based testing (test multiple genes at once)

B. Commercial laboratory – one PGx test at a time (e.g., CYP2C19 testing only)

C. In‐house testing (tests are processed by our institution’s pathology lab)

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If you currently offer pharmacogenetictesting, what type of laboratory do you use?

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Genes and

VariantsLogistics

Reporting of results Test cost

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Domains for evaluating laboratories

• What gene(s) is/are applicable to my clinical setting?

• What variants for each gene are interrogated and are they representative of my patient population?

• How are the genes aggregated for testing? (single gene, disease‐specific panel, broad panel testing)

• Can the laboratory provide a customized panel of genes?

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Pharmacogene and variant selection

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Current drug-gene pairs with CPIC Guidelines by disease state

Cardiology• Clopidogrel – CYP2C19• Simvastatin – SLCO1B1•Warfarin – CYP2C9 and VKORC1

Infectious disease• Abacavir – HLA‐B*57:01• Atazanavir – UGT1A1• PEG‐interferon – IL28B

Neurology• Carbamazepine – HLA‐B*15:02

• Phenytoin – CYP2C9, HLA‐B*15:02

Oncology• Thiopurines – TPMT• Capecitabine/5‐FU – DPYD• Rasburicase – G6PD

Pain management• Codeine – CYP2D6• Tramadol – CYP2D6• Tricyclic antidepressants –CYP2C19, CYP2D6

Psychiatry• Tricyclic antidepressants –CYP2C19, CYP2D6

• Selective serotonin reuptake inhibitors – CYP2C19, CYP2D6

Rheumatology• Thiopurines – TPMT• Allopurinol – HLA‐B*58:01

Solid organ transplant• Tacrolimus – CYP3A5

Respiratory• Ivacaftor – CFTR

https://cpicpgx.org/guidelines/





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Gene Lab A Lab B Lab C Lab D Lab E

CYP2C19 *2, *3, *4, *4B, *10, *17*2,*3,*4,*4B,*5,*6,*7,*8,*9,*10,*17

*2,*3,*4,*5,*6,*7, *8,*17

*2,*3,*4,*6,*8,*9, *10,*17

*2,*3,*17

CYP2C9*2, *3, *4, *5, *6, *8,

*11, *18*2,*3,*5,*6,*8,*11,

*27*2,*3,*4,*5,*6

*2,*3,*5,*6,*8,*11,*12

‐

CYP2D6

*2A, *2, *3, *4, *4N, *4M, *5, *6, *6C, *7, *8, *9, *10, *11, *12, *13, *14A, *14B, *15, *17, *18, *19, *20, *29, *31, *35, *36, *41, *42, *63, *64, *68, *69, *70, *91, *109, duplication

*2, *3, *4, *4M,*5, *6, *7, *8, *9, *10, *11, *12, *14A,

*14B, *17, *29, *35, *41, *56A, *56B,

duplication

*2,*2A,*3,*4,*5,*6,*7,*8,*9,*10,*11, *12,*14,*15,*17, *41, duplication

*2,*3,*4,*5,*6,*7, *9,*10,*11,*12*17,

*29,*41, duplication

*2,*3,*4,*5,*6, *9,*10, *11,*41,

duplication

CYP3A5 *3, *6, *7 *1D,*3,*3C,*6,*7 ‐ *2,*3,*6,*7 *3,*6,*7

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Variant selection

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Variant frequencies differ by population

CYP2C19 allele

African Allele Frequency

African American Allele

Frequency

Caucasian (European + North American) Allele

Frequency

Middle Eastern Allele

Frequency

East Asian Allele

Frequency

South/Central Asian Allele Frequency

Americas Allele Frequency

OceanianAllele

Frequency

*1d 33.10 57.00 62.10 64.80 57.60 48.50 67.00 28.60*2 14.20 18.30 14.60 13.10 29.30 33.10 13.10 54.90*3 0.80 0.30 0.60 2.60 8.60 1.60 0.30 13.90*4A 0.00 0.00 0.30 0.10 0.00 0.03*5 0.00 0.00 0.00 0.00 0.00 0.00*6 0.00 0.00 0.10 0.00 0.00 0.00*7 0.00 0.00 0.00 0.00 0.00 0.00*8 0.00 0.20 0.30 0.00 0.00 0.10*9 4.20 1.10 0.00 0.00 0.10*10 0.00 0.40 0.00 0.00 0.10*12 0.00 0.20 0.00 0.00 0.00*13 0.00 1.20 0.10 0.00 0.40*14 0.00 0.00 0.00 0.00 0.00*15 5.70 1.40 0.20 0.20 0.40*17 15.10 20.10 21.30 19.50 1.60 16.90 16.30 2.50*35 3.10 0.80 0.00 0.00 2.10

https://www.pharmgkb.org/page/cyp2c19RefMaterials


CYP2C19*2, *3, *4, *4B, *10,

*17*2,*3,*4,*4B,*5,*6,*7,*8,*9,*10,*17

*2,*3,*4,*5,*6,*7, *8,*17

*2,*3,*4,*6,*8,*9, *10,*17

*2,*3,*17

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Which lab has better coverage for a majority African American population?

CYP2C19 allele African Allele Frequency African American Allele Frequency

Caucasian (European + North American) Allele Frequency

*1d 33.10 57.00 62.10*2 14.20 18.30 14.60*3 0.80 0.30 0.60*4A 0.00 0.00 0.30*5 0.00 0.00 0.00*6 0.00 0.00 0.10*7 0.00 0.00 0.00*8 0.00 0.20 0.30*9 4.20 1.10 0.00*10 0.00 0.40 0.00*17 15.10 20.10 21.30


CYP2C19*2, *3, *4, *4B, *10,

*17*2,*3,*4,*4B,*5,*6,*7,*8,*9,*10,*17

*2,*3,*4,*5,*6,*7, *8,*17

*2,*3,*4,*6,*8,*9, *10,*17

*2,*3,*17

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Which lab has appropriate coverage for a majority Caucasian population?

CYP2C19 allele African Allele Frequency African American Allele Frequency

Caucasian (European + North American) Allele Frequency

*1d 33.10 57.00 62.10*2 14.20 18.30 14.60*3 0.80 0.30 0.60*4A 0.00 0.00 0.30*5 0.00 0.00 0.00*6 0.00 0.00 0.10*7 0.00 0.00 0.00*8 0.00 0.20 0.30*9 4.20 1.10 0.00*10 0.00 0.40 0.00*17 15.10 20.10 21.30





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Gene selectionGene Lab A Lab B Lab C Lab D Lab E Gene Lab A Lab B Lab C Lab D Lab EN 21 22 16 14 10 GRIK4 − − − −

ABCB1 − − − − HLA‐A − − − −

ADRA2A − − − HLA‐B − − − −

ANK3 − − − − HTR2A − − −

ApoE − − − − HTR2C − − −

CACNA1C − − − − IFNL3/IL28B − − − −

COMT MTHFR −

CYP1A2 − NUDT15 − − − −

CYP2B6 − − OPRK1 − − − −

CYP2C19 OPRM1 −

CYP2C9 − SLC6A4 −

CYP2D6 SLCO1B1 − −

CYP3A4 − SULT4A1 − − − −

CYP3A5 − TPMT − − − −

DPYD − − − − UGT1A1 − − − −

DRD2/ANKK1 − − UGT1A4 − − − −

F2 − − UGT2B15 − − −

F5 − − VKORC1 − −





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Gene selectionGene Lab A Lab B Lab C Lab D Lab E Gene Lab A Lab B Lab C Lab D Lab EN 21 22 16 14 10 GRIK4 − − − −

ABCB1 − − − − HLA‐A − − − −

ADRA2A − − − HLA‐B − − − −

ANK3 − − − − HTR2A − − −

ApoE − − − − HTR2C − − −

CACNA1C − − − − IFNL3/IL28B − − − −

COMT MTHFR −

CYP1A2 − NUDT15 − − − −

CYP2B6 − − OPRK1 − − − −

CYP2C19 OPRM1 −

CYP2C9 − SLC6A4 −

CYP2D6 SLCO1B1 − −

CYP3A4 − SULT4A1 − − − −

CYP3A5 − TPMT − − − −

DPYD − − − − UGT1A1 − − − −

DRD2/ANKK1 − − UGT1A4 − − − −

F2 − − UGT2B15 − − −

F5 − − VKORC1 − −

• What type of sample is required?• What is the turnaround time?• Are samples stored for future testing?• Are samples used for research purposes?

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Logistics

• What type of sample is required?–Blood

– Saliva

–Buccal

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Logistics


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Logistics

What approach is used for testing?

Reactive• Ordering test as drug therapy is initiated or failed– Delay before results are ready

• May need quick turnaround

Preemptive • Pharmacogenetic result available before prescribing– Available at point of care:

• Results already interpreted • Clinical decision support (CDS) provides relevant genetic results

• Turnaround time of weeks may be ok


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Logistics

• How are the results returned to a provider/patient?• Are the results easy to interpret for a provider/patient?

• Is the evidence for each recommendation available?• Does the evidence support the recommendations?• What education materials are available to aid in discussion of the results?

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Reporting of results

• How are the results returned to a provider/patient?–Printable PDF

– Interfaced directly to the EHR

–Dynamic online portal

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• How are the results returned to a provider/patient?• Are the results easy to interpret for a provider/patient?

• Is the evidence for each recommendation available?• Does the evidence support the recommendations?• What education materials are available to aid in discussion of the results?

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• How are the results returned to a provider/patient?• Are the results easy to interpret for a provider/patient?• Is the evidence for each recommendation available?• Does the evidence support the recommendations?• What education materials are available to aid in discussion of the

results?

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• How are the results returned to a provider/patient?• Are the results easy to interpret for a provider/patient?• Is the evidence for each recommendation available?• Does the evidence support the recommendations?• What education materials are available to aid in discussion of the

results?

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• Does the laboratory bill patient insurance directly?• What patient financial assistance programs does the laboratory

provide? • Does the laboratory provide a maximum cost for the patient?

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Test cost



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Test cost



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Test cost

• A. Knowing which gene(s) to test• B. Interpreting the laboratory results• C. Ensuring patients get reimbursed for pharmacogenetic testing

• D. Explaining pharmacogenetic test results to patients

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What is most challenging about using pharmacogenetic test results in your practice?

The selection of a laboratory to perform pharmacogenetictesting is influenced by several factors

1. Identifying the pharmacogenes and variants relevant to the practice setting

2. Matching clinical workflows with laboratory logistics

3. Understanding how results are reported

4. Considering test cost and reimbursements39

Conclusion

Documents

Laboratory Testing in Clinical Pharmacogenetics: How to Choose … · 2018/11/1 · Matching clinical workflows with laboratory logistics 3. Understanding how results are reported