Medivo genomics 101_no-notes

  • 1,231 views
Uploaded on

The purpose of the following program is to educate primary care physicians about molecular genetic tests and ensure that they have the relevant competencies to evaluate and order genetic tests and be …

The purpose of the following program is to educate primary care physicians about molecular genetic tests and ensure that they have the relevant competencies to evaluate and order genetic tests and be able to interpret the results of the molecular genetic test results for their patients.

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
1,231
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
0
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. Primary Care Genomics Education Program_101
    Introduction to
    Molecular Genetic Testing
  • 2. Educational Objectives
    Improve primary care clinicians comfort in ordering and using genetic tests in clinical practice.
    • Provide a methodology to enable physicians to evaluate the benefits and limitations of current molecular genetic tests.
    • 3. Prior to completing this program, please take the following Pre-Program evaluation :
    • 4. http://www.surveymonkey.com/s/M8LMJVH
    The content is aligned with published competencies in molecular genetic testing and genomic medicine for public health professionals. The program was developed using the most current publicly available resources.
  • 5. Chapter 1. Introduction to Genetics and the Role of Molecular Genetic Testing in Clinical Medicine
  • 6. Molecular Genetic Tests in Clinical Practice
    Genetic tests developed for >2200 diseases of which ~2000 are currently available for use in clinical settings
    >90% of human genetic variation are single nucleotide polymorphisms, SNPs, which can be assayed using molecular genetic tests.
    Family Planning
    &Perinatal Health
    Disease Diagnosis
    Predictive Trait
    or Disease
    Oncology
    Drug Response
    • Diagnosis
    • Disease
    • Prognosis
    • Drug Response
    • Hereditary
    colon cancer
    • Breast & ovarian
    cancer
    • BRCA 1,2
    • 7. Herceptin
    response
    Irinotecan toxicity
    • Cetuximab/
    panitumumab
    response
    • Preimplantation
    Genetic Diagnosis
    • Carrier Status
    • Newborn
    • Screening
    - Tay Sachs
    - Canavan
    - Cystic fibrosis
    - Sickle-cell anemia
    - Phenylketonuria
    • Factor V Leiden
    thromobophilia
    - Hereditary
    hemochromatosis
    syndrome
    • Huntington's
    - Thalassemias
    • Health
    • Assessment
    • Disease Risk
    - Heart disease
    - Stroke
    - Diabetes
    - Lung cancer risk
    • Metabolism
    • Response
    • Resistance
    • Toxicity
    - Warfarin response
    - Plavix resistance
    • Abacavir
    hypersensitivity
    - Tamoxifen
    - Resistance
    - Imuran
    - Allomap Heart
    - Transplant
  • 11. Optional Basic Science Review
    Click on the topics below to dive into more detail.
    Gene structure and function (slide 26)
    DNA, RNA, structure, and function
    Why Genetic Variation Doesn't Always Cause Disease (slide 27)
    Mutation and variation
    The science and application of genomics to medicine (slide 28)
    SNP’s and their role in variation
    Methodology of genetic testing (slide 29)
    Sample collection and analysis
  • 12. Molecular Genetic Tests are Regulated at the Federal Level by both CLIA and the FDA
    CMS and CLIA
    CMS regulates laboratories that conduct tests using Laboratory Developed Tests [LDTs]
    Establish quality standards for laboratory testing and accreditation program for clinical labs
    CLIA-certification requirements depend upon complexity of tests performed to ensure labs/analysts/operators are competent to perform tests of different complexity
    3 categories: moderate/high/waived
    FDA [CDER]
    Regulates to ensure tests are safe and effective
    Tasked through FFDCA with oversight of IVDs, ASRs, categorizing complexity of LDTs
    Categorizes tests into 3 classes according to level of control needed to assure safety and effectiveness
    Genetic tests are considered Class I (most complex)
    IVDMIA [In vitro diagnostic multivariate index assay]
    Test that assays multiple variables such as gender/age/weight + results of genetic testcomputer algorithm=health risk assessment
    These are the most controversial types of tests
  • 13. Personal Privacy, Genetic Information and Legal Protection
    Informed Consent
    Required prior to ANY genetic testing or molecular genetic analysis
    Consent laws created and enforced at the state government level
    Required even for population level analysis, employers, etc.
    HIPAA
    Covers individual's right to privacy for their medical and health information includes information related to genetic testing
    GINA
    Genetic Information Nondiscrimination Act signed into law 2008
    Protects individuals from misuse of genetic information in health insurance by insurers and in employment by employers
    Designed to removed barriers to the appropriate use of genetic services by the public
  • 14. There are Some Key Points to Consider in the Interpretation and Limitations of Molecular Genetic Tests
    Reference range
    What is the normal prevalence of a genotype for a given population?
    Does the reference population match the individual receiving the test? Is information available for additional populations?
    Limitations
    Unrecognized sequence variations or polymorphisms can affect ability of tests to detect or distinguish the genotypes being analyzed, leading to false-positive or false-negative test results
    Clinical validity of each test
    Ability of test to diagnose or predict risk for a particular health condition or drug response
    Measured by sensitivity and specificity, predictive value for given disease
    Influenced by prevalence of disease or health condition, penetrance, and genetic and environmental modifiers
    Sample Package Insert for CYP2C19 for Expected Values/Reference Range
  • 15. Genetic Variation May or May Not Be Expressed Clinically in the Individual
    Disease Outcome
    Probabilistic
    Predictable
    Mendelian
    Single Gene
    Mixed
    non-Mendelian
    Complex
    Mode of Inheritance
    Penetrance
    High
    Low
    # Genes Analyzed
    One
    Many
    Low
    Trait Prevalence
    High
  • 16. Chapter 2. Categories of Genetic Testing Currently in Broad Use including Common Questions for Each Test
  • 17. Common questions to be able to answer when using genetic and genomic tests:
    • What is the test analyzing?
    • 18. What is it not analyzing?
    • 19. What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk, predictive vs probabilistic risk.
    • 20. Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    • 21. Is the test looking for a single mutation or all known mutations for a gene?
    • 22. How does the information from the genetic test fit within an individual's family health history?
    Categories of Genetic Testing in Use Issues and Common Questions
  • 23. Diagnostic Test to Confirm Disease:Suspected Thrombophilia
  • 24. Common questions to be able to answer when using this genetic test:
    What is the test analyzing?
    Specific known mutations for thrombophilia.
    What is it not analyzing?
    All known mutations for thrombophilia.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk
    If the test is positive for a mutation for thrombophilia it can be diagnostic of suspected thrombophilia.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    Yes, the test can help diagnose patients who carry a mutation that increases their risk of a clotting disorder and can be counseled and managed appropriately.
    How does the information from the genetic test fit within an individual's family health history?
    Thrombophilias have Mendelian inheritance – a family health history can help identify other potential family members with suspected thrombophilias.
  • 25. Drug Response: Warfarin
  • 26. Common questions to be able to answer when using this genetic test:
    What is the test analyzing?
    The known genetic markers that determine warfarin metabolism.
    What is it not analyzing?
    All the possible genes responsible for warfarin metabolism.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    The test results can be used, in conjunction with other clinical information, to guide warfarin dose selection for individuals in need of anticoagulation, potentially shortening the time needed to reach a stable, effective dose. Studies have also shown that using genetic test information to calculate dosage can minimize the risk of adverse bleeding events, which occurs in 10-16% of patients using warfarin.
    How does the information from the genetic test fit within an individual's family health history?
    These genetic markers exhibit Mendelian inheritance so if a patient has a mutation, family members should be notified if clinically indicated.
  • 27. Predictive for Disease Risk/Phenotypic Trait-Polygenic Dyslipidemia-
    Use of the term mutation means that changes in the DNA [genotype] are phenotypically pathologic, eg Huntington's disease, cystic fibrosis, thus it is more acceptable to use the term allelic variation or single nucleotide polymorphisms for genetic variation to include the full range of genetic variation expression from disease-causing to benign. The most common variant at a genetic marker in a given population is considered the 'wild type' with minor allelic frequencies >1% considered polymorphisms.
  • 28. Common questions to be able to answer when using this genetic test:
    What is the test analyzing? Multiple common genetic variants that can contribute to a risk for dyslipidemia.
    What is it not analyzing? The genetic test is not diagnostic test for dyslipidemia.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk The genetic analysis provides insights into an individual's relative risk for developing dyslipidemia.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change? Yes, the results can be used to motivate patients to improve their health and potentially decrease their chances of developing the condition.
    How does the information from the genetic test fit within an individual's family health history? Dyslipidemia is the result of an individual's genetic background and environmental influences, such as diet/exercise/lifestyle choices. The family health history is important to inform those environmental influences that can be modified
  • 29. Family Planning and Perinatal Health:Newborn Screening for Cystic Fibrosis
  • 30. Common questions to be able to answer when using this genetic test:
    What is the test analyzing? A panel of known mutations in the CFTR gene.
    What is it not analyzing? All known mutations in the CFTR gene.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk, predictive vs probabilistic risk.The information learned will establish if an individual has mutations in the CFTR gene that require further confirmation with a sweat test to diagnose CF.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?A qualitative genotyping test which provides information intended to be used as an aid in newborn screening and in confirmatory diagnostic testing in newborns and children.
    Is the test looking for a single mutation or all known mutations for a gene? All currently known mutations, but not all possible mutations.
    How does the information from the genetic test fit within an individual's family health history?
    Yes, CF is inherited in an autosomal recessive gene and family members can be tested to determine if they also carry mutations in the CFTR gene.
    In newborn screening the CF gene test provides confirmation for the trypsinogen test or sweat test about the specific mutations in the CFTR gene.
    Both genetic and environmental factors likely influence the severity of the CF which might help explain why some people with cystic fibrosis are more severely affected than others.
  • 31. Diagnostic or Predictive for Oncology-K-RAS Mutations-
  • 32. Common questions to be able to answer when using this genetic test:
    What is the test analyzing?
    Known mutations in the K-RAS gene that decrease response to anti-EGFR therapies.
    What is it not analyzing?
    All mutations that might contribute to the decrease in therapeutic response.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk
    Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occur in 40% of colorectal cancers.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    Yes – will help determine if a patient will respond to an EGFR therapy.
    How does the information from the genetic test fit within an individual's family health history?
    Cancer is a complex disease and has both environmental and inherited contributors.
  • 33. Looking at Genomic testing with a trained eye
    Recognize the category of test being performed
    Understand the utility and limitations of the test category
    Explain the relevance of the test and it’s utility and limitations to the patient
    Thank you for your participation. Please complete the following post-program evaluation.
    http://www.surveymonkey.com/s/TCJL9JZ
  • 34. Citations1
    American Board of Medical Genetics [ABMGMolGen]. Content outline for Clinical Molecular Genetics Certification Examination. Accessed 11.10.2010. Available at http://www.abmg.org/2011/cert_essentials.shtml
    Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science. 2008;322(5903):881-8.
    Autogenomics Package Insert. INFINITI CYP2C19 Assay. Available at: www.autogenomics.com.
    Bokemeyer C, et al. (February 2009). Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J ClinOncol. 2009;27 (5): 663–71.
    Centers for Disease Control and Prevention [MMWR]. Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions. MMWR 2009;58(No. RR-6):[1-35].
    Center for Disease Control [CDC OPHG]. Office Public Health Genomics, Genomics Translation, Genomic Workforce Competencies, 2001. Genomic competencies for public health professionals in clinical services evaluating individuals and families. Accessed 11.10.2010. Available at http://www.cdc.gov/genomics/translation/competencies/
    CDC Public Health Genomics. Genetic Testing. Accessed 11.15.2010. Available at: http://www.cdc.gov/genomics/gtesting/.
    CETT. Guidelines for developing CETT materials. Accessed 11.15.2010. Available at http://www.cettprogram.org/
    Chen B, Gagnon M, Shahangian S, Anderson NL, Howerton DA, Boone JD; Centers for Disease Control and Prevention (CDC). Good laboratory practices for molecular genetic testing for heritable diseases and conditions. MMWR Recomm Rep. 2009 Jun 12;58(RR-6):1-37; quiz CE-1-4.PMID: 19521335.
    de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem. 1994;269(22):15419-22.
    FDA. Device Regulation and Guidance. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htm Accessed 12.10.2010.
    FDA. IVD Regulation. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistanceOverviewofIVDRegulation/ Accessed 12.10.2010.
    FDA CLIA Process. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/CLIAComplexityProcess/ Accessed 12.10.2010.
    FDA. Table of Pharmacogenomic Biomarkers in Drug Label. Accessed 12.10.2010.
    Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. Feero WG, Guttmacher AE, Collins FS. Genomic Medicine-An Updated Primer. N Engl J Med. 2010;362:2001-2011.
    Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001;3:139–48.
    Grossniklaus D. Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing: Test Category: Pharmacogenomic (Treatment) PLoSCurr. 2010 September 14; 2: RRN1155. doi:10.1371/currents.RRN1155.
    Guttmacher AE, Collins FS. Genomic Medicine – a primer. N Engl J Med. 2002;347:1512-1520.
  • 35. Citations2
    Handoff LA, Junkins HA, Hall PN, Mehta JP, and Manolio TA. A Catalog of Published Genome-Wide Association Studies. Accessed 12.3.2010. Available at: www.genome.gov/gwastudies. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-7.
    Javitt G, Katsanis S, Scott J, Hudson K. Developing the Blueprint for a Genetic Testing Registry. Public Health Genomics. 2010;13:95-105.
    Kathiresan et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41(1)56-65.
    Lesko LJ, Zineh I, Huang S-M. What is Clinical Utiliity and Why Should we Care? ClinPharm Therapeutics. 2010;88(6):729-733.
    Lièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66 (8): 3992–5.
    L. van Epps, PhD, Heather (Winter, 2008). "Bittersweet Gene: A gene called KRAS can predict which colorectal cancers will respond to a certain type of treatment—and which will not.". CURE (Cancer Updates, Research and Education).
    Kujovich J. Factor V Leiden Thrombophilia. GeneReviews March 9, 2010. Accessed 12.7.2010. Available at http://www.ncbi.nlm.nih.gov/sites/GeneTests/review/disease/factor%20V?db=genetests&search_param=contains
    National Center for Biotechnology Information. GENETests. Educational materials. Accessed 11.16.2010. Available at http://www.ncbi.nlm.nih.gov/projects/GeneTests/static/concepts/teachtool/teachintro.shtml
    National Coalition for Health Professional Education in Genetics [NCHPEG Core]. Core competencies in Genetics for Health Professionals. Third Edition. September 2007. Accessed 11.10.2010. Available at http://www.nchpeg.org/index.php?option=com_content&view=article&id=94&Itemid=84
    National Coalition for Health Professional Education in Genetics [NCHPEG Nutr]. Genetics and Nutrition-A Resource for Dietetic Faculty and Practitioners. 2010. Accessed 11.10.2010. Available at http://www.nchpeg.org/nutrition/ NCBI. Genetests Resource Center. Available at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests.
    The Genetic Information Nondiscrimation Act (GINA). Information for Researchers and Health Care Professionals. Accessed 12.10.2010. Available at: http://www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf
    Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360 (14): 1408–17.
    U.S. Department of Energy Genome Programs. SNP Fact Sheet. Accessed 12.10.2010. Available at: http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml
    Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007 Jul 9;167(13):1414-9.
  • 36. Appendix
    Optional Deep Dive
  • 37. Gene Structure and Function
    DNA [deoxyribonucleic acid]
    Double helix of complementary nucleotides [base+sugar+phosphate]
    adenine (A), cytosine (C), guanine (G), thymine (T)
    RNA [ribonucleic acid]
    A, C, G, uracil (U)
    Specific base pairing rules
    DNA: A-T, C-G
    RNA: A-U, C-G
    Gene Structure
    transcription occurs 5'  3'
    promoter contains sequences for polymerases to initiate transcription DNA transcribed into mRNA = exons + introns
    UTR or untranslated regions of the DNA regulate transcription rates
    exons code for protein when translated
    introns or intragenic sequences regulate mRNA splicing
    Gene Function
    Storage of DNA code
    DNA -> mRNA -> protein
    For a basic overview, click on the following links:
    http://en.wikipedia.org/wiki/Gene
    http://www.ornl.gov/sci/techresources/HumanGenome/project/info.shtml
    Return to slide 5 »
  • 38. Why Genetic Variation Doesn't Always Cause Disease
    Redundancy in genetic code for DNA -> RNA -> protein means that single nucleotide polymorphisms may or may not change the expression and/or function of a protein
    Types of Genetic Variation
    Silent – does not alter amino acid GCC -> GCG
    Missense – substitution of an amino acid AAA -> AAC
    Nonsense – creates a stop codon for premature termination of translation TAT -> TAG
    Impact of Genetic Variation
    Synonymous
    variation does not alter gene expression or protein function
    Nonsynonymous
    variation alters protein function
    information, click on the following link:
    http://www.ornl.gov/sci/techresources/HumanGenome/faq/snps.shtml
    Return to slide 5 »
  • 39. Clinical Relevance of Genetic Variation: Pharmacogenetics
    Single nucleotide polymorphisms, SNPs, can be used to understand an individual's response to drugs.
    Example: P450 CYP2C19 gene polymorphism in exon 5 associated with variable drug response
    • Variant allele SNP 19154 G>A *2
    SNP creates aberrant splice site which ultimately results in a premature stop codon
    Allelic Function
    Wild type allele *1
    Variant allele reduced metabolism *2
    Variant allele no metabolism *3
    Allelic variation associated with different drug metabolizer states:
    Extensive metabolizer [normal] *1/*1
    Intermediate metabolizer *1/*2
    Poor metabolizer *2/*3
    For more information, click on the following links:
    http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml
    http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm
    Return to slide 5 »
  • 40. Methodology For Molecular Genetic Analysis of SNPs
    PCR principles
    Sample Path: Collection to Result
    Molecular Genetic Analysis Results
    Whole Blood or Buccal Swab or Saliva Sample/Cheek Cells
    DNA Purification
    DNA Amplification via Polymerase Chain Reaction (PCR)
    Microarray-based or PCR-based genotyping
    Genetic Analysis Results for SNPs Variants
    WT
    a-t-c-g-t-t-c-a-a-t-t
    Sample
    a-t-c-g-t-t-a-t-t-a-a
    Microarray
    Variant allele for GeneX nucleotide position: 1917
    SNP polymorphism: C>A
    Allelic designation: *2
    Return to slide 5 »