Ensuring the Quality of Genetic Testing

ICORD Meeting September 14, 2007

Lisa Kalman, PhDCoordinator, GeT-RM

CDCLKalman@cdc.gov

How does the genetic testing How does the genetic testing laboratory know that a test is laboratory know that a test is working properly and will give working properly and will give

accurate results?accurate results?

Reference or Quality Control (QC) Reference or Quality Control (QC) materials are used to:materials are used to:

Assess whether the genetic test is working Assess whether the genetic test is working properly and can detect genetic alterations properly and can detect genetic alterations

(mutations) (mutations)

Quality ControlQuality Control

What is the Ideal Reference What is the Ideal Reference Material for Genetic Testing?Material for Genetic Testing?

(Ideally)(Ideally) Blood from patients with characterized Blood from patients with characterized mutations or alleles known to cause the disordermutations or alleles known to cause the disorder

(Practically)(Practically) Material that closely resembles a Material that closely resembles a patient sample so it can be used to monitor and patient sample so it can be used to monitor and evaluate all steps of the testing processevaluate all steps of the testing process

Could be a cell line or purified DNACould be a cell line or purified DNA Studied extensively and proven to contain Studied extensively and proven to contain

particular mutations(s) (alleles)particular mutations(s) (alleles)

Reference materials are Reference materials are alsoalso important for:important for:

Comparison of results between laboratoriesComparison of results between laboratories Proficiency testing samplesProficiency testing samples Test calibrationTest calibration Development of new genetic testsDevelopment of new genetic tests Validation of new genetic testsValidation of new genetic tests

Reference Materials for Reference Materials for Genetic TestingGenetic Testing

Genetic testing volume is increasingGenetic testing volume is increasing Many new tests are being introducedMany new tests are being introduced

However…..However…..

Positive controls samples arePositive controls samples areNOTNOT publicly available for most publicly available for most genetic tests! genetic tests! (and even fewer have been(and even fewer have been verified)verified)

Collected information about 35 US testing labsCollected information about 35 US testing labs

All clinical labs tested for at least the ACMG All clinical labs tested for at least the ACMG recommended 23 CF allelesrecommended 23 CF alleles

Identified 102 different CF alleles tested in US Identified 102 different CF alleles tested in US clinical labsclinical labs

There are cell lines for only 42 allelesThere are cell lines for only 42 alleles

60 alleles not available as cell lines 60 alleles not available as cell lines !!

Example Example - Cystic Fibrosis - Cystic Fibrosis (CF) Genetic Testing(CF) Genetic Testing

Other ExamplesOther Examples

Fragile X and Huntington DiseaseFragile X and Huntington Disease

Genetic tests where the size of the gene is Genetic tests where the size of the gene is measured measured

VERYVERY technically difficult tests technically difficult tests

Precise size measurement is needed for Precise size measurement is needed for proper diagnosisproper diagnosis

Few characterized reference Few characterized reference materials available!materials available!

When No ReferenceWhen No Reference Materials are Available….. Materials are Available…..

Labs use previously assayed patient samples Labs use previously assayed patient samples Problem-Problem-how do you know that they were how do you know that they were assayed correctly if the lab lacks controls?assayed correctly if the lab lacks controls?

Synthetic controls are available for a few testsSynthetic controls are available for a few testsProblem-Problem- synthetic DNA may not perform the synthetic DNA may not perform the same as human DNA in the assaysame as human DNA in the assay

Sometimes labs run assays without adequate Sometimes labs run assays without adequate controlscontrols

Problem-Problem- not ideal, may increase chance of not ideal, may increase chance of errors!errors!

Genetic Testing Reference Genetic Testing Reference Material Program (GeT-RM)Material Program (GeT-RM)

A CDC-based program to improve the A CDC-based program to improve the availability of reference materials for availability of reference materials for

genetic testinggenetic testing

Collaboration with genetic testing communityCollaboration with genetic testing community

Academic and clinical genetic testing labsAcademic and clinical genetic testing labs Government agenciesGovernment agencies Cell repositoriesCell repositories IndustryIndustry Professional organizationsProfessional organizations

Roles of GeT-RMRoles of GeT-RM Improve and coordinate information exchange Improve and coordinate information exchange

about reference materialsabout reference materials

Monitor reference material needs of genetic Monitor reference material needs of genetic testing communitytesting community

Facilitate submission, development and Facilitate submission, development and characterization of reference materials characterization of reference materials

Develop a sustainable community process for Develop a sustainable community process for continued reference material developmentcontinued reference material development

GeT-RM WebsiteGeT-RM Websitehttp://wwwn.cdc.gov/dls/genetics/qcmaterials/default.aspxhttp://wwwn.cdc.gov/dls/genetics/qcmaterials/default.aspx

Provides information about:Provides information about: Availability and validation status of a variety of Availability and validation status of a variety of

reference materialsreference materials Reference material needsReference material needs How to contribute potential reference materialsHow to contribute potential reference materials Professional and regulatory guidanceProfessional and regulatory guidance ReferencesReferences CDC’s efforts to improve the quality of genetic testingCDC’s efforts to improve the quality of genetic testing

Solicits input from the genetic testing communitySolicits input from the genetic testing community

Coriell Institute for MedicalCoriell Institute for Medical ResearchResearch

http://ccr.coriell.org/Default.aspxhttp://ccr.coriell.org/Default.aspx

National Institute of General National Institute of General Medical Sciences (NIGMS) Human Medical Sciences (NIGMS) Human

Genetic Cell RepositoryGenetic Cell Repositoryhttp://ccr.coriell.org/Sections/Collections/NIGMS/?SsId=8http://ccr.coriell.org/Sections/Collections/NIGMS/?SsId=8

Non Profit -Supported by NIHNon Profit -Supported by NIH

Coriell distributes DNA and cell line samples to facilitate genetic Coriell distributes DNA and cell line samples to facilitate genetic research and improve laboratory quality since 1972research and improve laboratory quality since 1972

GeT-RM Reference Material GeT-RM Reference Material Development ProjectsDevelopment Projects

Ashkenazi Jewish PanelAshkenazi Jewish PanelRecently completed characterization of 27 cell lines Recently completed characterization of 27 cell lines from Coriell as reference materials for genetic testing from Coriell as reference materials for genetic testing of 9 disorders common in the Ashkenazi Jewish of 9 disorders common in the Ashkenazi Jewish populationpopulation

Tay-sachs diseaseTay-sachs disease Canavan diseaseCanavan disease Glycogen storage disease type 1aGlycogen storage disease type 1a Familial dysautonomiaFamilial dysautonomia Mucolipidosis type IVMucolipidosis type IV Niemann-Pick disease type ANiemann-Pick disease type A Fanconi anemia group CFanconi anemia group C Bloom syndrome Bloom syndrome Gaucher diseaseGaucher disease

Huntington disease and Huntington disease and Fragile XFragile X

The GeT-RM has completed The GeT-RM has completed characterization of:characterization of:

14 Huntington cell lines from Coriell14 Huntington cell lines from Coriell

21 fragile X cell lines from Coriell 21 fragile X cell lines from Coriell

For use as reference materials!For use as reference materials!

GeT-RM Current and Future GeT-RM Current and Future Reference Material Reference Material

Development ProjectsDevelopment Projects

Cystic fibrosisCystic fibrosis Breast CancerBreast Cancer Newborn Screening disordersNewborn Screening disorders Others???Others???

Continued ReferenceContinued Reference Material Development…Material Development…

Big Problem…Big Problem…

Lack of available cell lines!!!!!Lack of available cell lines!!!!!

Development of New Development of New Reference MaterialsReference Materials

2 Methods2 Methods

1.1. Establish new cell linesEstablish new cell lines

2. Identify mutations in existing cell lines2. Identify mutations in existing cell lines

Problem- Problem- Limited access to patient blood samples!Limited access to patient blood samples!

GeT-RM is expanding into other GeT-RM is expanding into other areas of molecular testing -areas of molecular testing -

Molecular OncologyMolecular Oncology

Infectious DiseaseInfectious Disease

Biochemical Genetic TestsBiochemical Genetic Tests

!!GeT-RMGeT-RM::

http://wwwn.cdc.gov/dls/genetics/qcmaterials/default.aspxhttp://wwwn.cdc.gov/dls/genetics/qcmaterials/default.aspx