# Presentation: 691394

## Advances in Proficiency Testing for Genetic Laboratory Sciences

- Brad Popovich
- Senior Director, Diagnostics and Pharmacogenetic
- Xenon Genetics
- Vancouver, British Columbia, Canada

## Sir William Osler, 1892

- “If it were not for the great variability among individuals medicine might as well be a science and not an art”

## Advances in Proficiency Testing for Genetic Laboratory Sciences

- Session Outline:
- Overview of genetic testing
- ACMG/CAP PT programs for genetic testing
- Challenges in genetic PT
- Logistical issues
- Economic challenges
- Conclusions

## Three kinds of genetic tests

- Cytogenetic
- DNA
- Biochemical

## Hereditary Mutations

## Somatic Mutations

## Value of Interlaboratory Comparison Program

- Provides reassurance of laboratory quality.
- Performance outside the norm can be identified and corrective action taken even when internal comparisons are consistent over time (good precision/poor accuracy).
- Comparative statistics may detect biases between different instruments/reagents/techniques.
- Overall statistics objectively reflect state of the art in laboratory practice, as opposed to arbitrary standards as set by outside agencies.

## Types of Genetic PT Programs

- Formal
- American College of Medical Genetics/College of American Pathologists (ACMG/CAP)
- European Molecular Genetics Quality Network (EMQN)
- Human Genetics Society of Australasia
- Informal
- Interlaboratory exchange programs
- GeneTests  (www.genetests.org)
- Regional programs
- PacNoRGG
- Professional organizations
- ACMG
- AMP
- SIMD

## CAP Proficiency Testing Program in Molecular Pathology

- Molecular Oncology (MO)
- In Situ Hybridization (ISH)
- Bacteria, Mycobacteria, Viruses (ID, HIV/HV2, HC5, HC6)
- Fluorescence In Situ Hybridization (CYF, CYG)
- Molecular Genetics (MGL)
- Forensic DNA Databases (DNA)
- Forensic Identity (FID)
- Parentage (PI)
- Molecular HLA-A, B, C Typing (ML)
- Molecular HLA-DR, DQ, DP Typing (DL)
- Bone Marrow Engraftment (ME)

## ACMG/CAP Biochemical and Molecular Genetics Resource Committee 

- CAP
- Wayne Grody (MGL)
- Chair
- John Eckfeldt (BGL)
- Jeff Kant (MGL)
- Ron McGlennen (MGL)
- Walter Noll (MGL)
- Tim Stenzel (MGL)
- CAP Fellow
- Shuji Ogino (CAP Fellow)

- ACMG
- Brad Popovich (MGL)
- Vice Chair
- Robert Desnick (BGL)
- Steve Goodman (BGL)
- Bill Nyhan (BGL)
- Tom Prior (MGL)
- Karen Snow (MGL)
- AACC Liaison
- Elizabeth Rohlfs

## Committee Charge

- Develop, maintain and enhance proficiency testing program to reflect the state of the art in both biochemical and molecular genetics
- Function as a resource to a variety of CAP and ACMG committees and commissions
- Develop an interface with various agencies and organizations concerned with defining and maintaining excellence in both biochemical and molecular genetics
- Contribute to the continuing education of the members of the CAP and ACMG through Surveys, critiques, publications, and participation in CAP and ACMG education programs

## MGL Survey History 2/2002

## MGL Enrollment

## Demographics of MGL-B 2001

- MGL-B 2001
- 217 participating labs
- 192 responses received
- US = 143
- International = 74

- Countries represented
- South Africa
- Brazil
- Canada
- Japan
- Australia
- Germany
- Chile
- Singapore
- South Korea
- France
- US

## MGL Program 1998-2002 Challenges per year (# of samples/challenge)

## PROPOSED SPECIMEN MODULARIZATIONACMG/CAP PT PROGRAM

## MGL-B 2001 Participation / Disease

- 217 Total Participants
- 192 Responses Received

## ADOPTED SPECIMEN MODULARIZATIONACMG/CAP PT PROGRAM 2002

- 17 Analytes
- 3 Specimens per challenge
- 2 times /year

| Module 1 | Module 2 | Module 3 |
| --- | --- | --- |
| FV | CF | BRCA1 |
| PT | DMD/BMD | BRCA2 |
| MTHFR | FA | MEN2 |
| FX | HD |  |
| PW/AS | DM |  |
| HH | RhD/E |  |
|  | HbA/C |  |
|  | SMA |  |
|  | SCA |  |

## Participant Costs for MGL and Modularization

- Costs:
- 2000	$812
- 2001	$1,200
- 2002: Modules introduced
- #1	$800
- # 2	$1,000
- # 3	$850
- Modules ultimately designed to keep PT costs lowest for the majority of participants

## Participation and Enrollment Fees for  2002 ACMG/CAP PT Program

## MGL Grading Started in 2001

- ≥10 responses necessary for grading
- Grading based on 80% consensus
- Grading for presence or absence of:
- Proper allele (SNPs): CF, FV, PT, etc.
- Exons: DMD, SMA, etc.
- Mutational status (i.e. genotype/phenotype interpretation): SCA, FX, DM, HD, etc.
- Alleles not (yet) graded for some analytes, examples:
- Fragile X: FRAXA
- MEN2: RET

## Grading CriteriaQuestions and Challenges

- Is the 80% rule acceptable for labs performing germ line genetic testing?
- Should PT performance be “coupled” to lab accreditation?
- Should the ACMG and CAP be proactive in educating MGL participants?
- Should special emphasis be placed on labs with sub-optimal performance?

## Special Challenges in Providing PT for Genetic Testing

- Lack of validated control materials
- ATCC
- Coriell
- Other cell repositories

## Select Genetic Diseases with Characterized Mutations Available Coriell Cell Repository

## Special Challenges in Providing PT for Genetic Testing

- Lack of validated control materials
- ATCC
- Coriell
- Other cell repositories
- Lack of any control materials for some analytes
- CF

## ACMG Recommended CF Mutation Panel

- ACMG 25 Mutation Panel based on >0.1%frequency world wide

- 2 CDC grants awarded to address lack of appropriate control materials

## Conclusions

- Standards and Guidelines: CRITICAL
- Enable “coupling” of PT with accreditation
- Must be quickly adaptable in fast moving field such as genetic testing
- Lab inspectors must be knowledgeable
- Should board certification be required for inspectors?
- Should ordering physicians be able to access relevant PT results for genetic testing?
- EDUCATION, EDUCATION, EDUCATION!!!

## Conclusions

- Enlightened
- Thank you