Ira M' Lubin, PhD, FACMG

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Ira M. Lubin, PhD, FACMG
Laboratory Practice Evaluation and Genomics
Branch Division of Public Health Partnerships,
NCHM, CoCHIS Centers for Disease Control and
Prevention
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Genetic Testing Provider's Perspective
What is communicated?
What should be communicated?
Diagnostic? Predictive?
Professional Guidance?
Test Order
Health care provider
Genetic counselor
Test Report
(direct to consumer)
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Agenda
1. Define case studies F Diagnostic Testing F
Carrier Testing 2. Define issues F What should
a result report provide? F Current guideline -
strengths and weaknesses F Consider a framework
for improving reports 3. The "Details" Use case
studies to highlight 1. Technological
implications 2. Integration with other types of
information (including what makes results
probabalistic) 3. "Clear" language? 4. Next
steps?
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Case Studies Developed
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What do we want from a result report?
A report effectively able to communicate 1.
Patient identifier 2. The analytic test
result 3. Indication for testing 4.
Interpretation of the result F genotype /
phenotype correlation F heritability F
generally not a medical management decision 5.
Limitations of the analytic test and interpretive
component 6. Follow up actions (testing,
counseling) and family implications
Certain national regulations may limit this
level of communication
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Current Guidelines Elements well defined
Administrative Information
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Current Guidelines Elements well defined
Specimen and Test Order Information
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Current Guidelines Elements well defined
Interpretation, Recommendations, and Other
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How good have laboratories been in
including these recommended elements?
1999 2000 2001 2002 n149 n173 n
193 n198 Name 97 97 97 97 Date of
birth 74 85 87 91 Place of
birth/Ethnic origin 10 30 43
53 Sampling/arrival date 38 63 65
80 Nature of the sample 47 59 66
73 Sample number 80 86 92 92 Date of
report 78 84 85 85 Reason for
testing 63 69 62 78 Genotype 99 100
98 97 Interpretation of the
data 89 90 91 89 Signature 86 87 8
9 89 List of mutations tested 76 81 82
85 Method used 55 64 74 84 Mutation
detection rate 47 43 53 80
EU CF Scheme
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Limitations
1. Far less guidance in how to effectively
communicate 2. Lack of specificity for
particular technology platforms
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Let's take a closer look - US Study
State With Participating Laboratory
2004 CAP PT 79 participants Our study (27
labs) All subscribe to CAP PT
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Diagnostic Case Studies
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Diagnostic Testing Rule in versus Rule out
not all laboratories perform diagnostic testing
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Technology Platforms Detection Rate Implications
1. Direct mutation analysis (limited number of
mutations) F PCR/ restriction InvaderTM 2.
Direct mutation analysis (expanded number of
mutations) F MASDA 3. Sequence screening prior
to sequence analysis F i.e., TTGE 4. Sequence
analysis
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InvaderTM Technology
ISOTHERMAL
30-50 probes are cleaved per target per minute
amplification is gt1000 in 1 hour
Company website www.twt.com (Third Wave
Technologies)
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InvaderTM Technology - Issues
1. Can be performed in non-specialty setting 2.
Initial assay - inherent false positive
rate (requiring confirmatory testing) 3. Next
generation claimed no confirmatory testing
necessary 3. For some laboratories, Positives
referred / Negatives reported directly
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Multiplex allele-specific diagnostic assay
(MASDA)
Issues 1. Sensitivity / Specificity (controls?
) 2. Detection rate
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DNA Sequencing
Reaction
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What are the recommendations for reporting
sequence variations?
source ACMG / CLSI (NCCLS) MM9-A
1. Sequence variation is previously reported and
is associated with the disorder 2. Sequence
variation is previously unreported but is of the
type expected to be associated with the
disorder 3. Sequence variation is previously
unreported and is of unknown significance 4.
Sequence variation is previously reported and is
known to be a neutral variant
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Reporting a Diagnostic Result
Patient Bobby 384910kb CgtT finding clinical
symptoms of CF
Format 1 "The patient is at least a carrier of
CF consistent with being unaffected. However,
a second mutation cannot be ruled out." Format
2 "The patient has been identified as a CF
carrier" Format 3 "One CF mutation was
identified. This result does not exclude a
diagnosis of CF"
Would adoption of a standard nomenclature result
in clearer communication?
This text is not unique to any single laboratory
report
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What is reported out?
Disease associated mutation reported Novel
variant reported Coding mutation of unknown
significance varies Non-coding mutation of
unknown significance varies Poly-T status
varies
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Carrier Testing Case Studies
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Recommended Carrier Screening Panel for Cystic
Fibrosis
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Carrier Testing Who is at risk What is the
risk?
not all laboratories perform testing for patient
w/ fam hx or patient w/carrier partner
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Carrier Testing Determining Risk for Disease to
Future Children
Unaffected
Affected
Carrier or Unaffected
Patient
?
Genetics in Medicine, March/April 2001, Vol. 3
No. 2 149-154
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Reporting a Carrier Test Result
Typical of Carol and Georgia / no mutations, /-
fam. hx
Format 1 "Based on the pedigree provided, the
patient has a risk of xx. Risk is reduced by
xx by this test resulting in a residual risk of
xx based on her reported ethnicity." Format
2 "There is no detectable CFTR gene mutation,
decreasing the probability of being a
carrier"..........."An expanded mutation panel is
available. Format 3 "Based on this result,
there is not a high risk for having a child
affected with CF.

This text is not unique to any single laboratory
report
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Carrier Testing Reporting Issues
1. If mutation found - genotype/ phenotype
correlation - family implications? 2. If
mutation not found - detection rate
implications - family history - assay
sensitivity / specificity - race / ethnicity
considerations - recommendations for follow up
testing?
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Follow up issues discussed in reports?
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Where we are today
Laboratories communicate concepts in their
written reports in different ways. 1. Lack of
standard nomenclature in communicating results
results in terms of their genetic and
phenotypic meaning. 2. There are both general
and platform/clinical-specific reporting issues
that need to be considered. 3. Quality
indicators are needed to assess
reporting effectiveness - take into account
clinician perspective
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General Considerations - a Template?
1. The analytic test result F single mutation
/ multiple SNPs / other 2. Indication for
testing (patient family) F directs laboratory
to most appropriate technique and
interpretation 3. Interpretation of the
result F genotype / phenotype correlation F
risk presentation F prognosis 4. Limitations of
the analytic test and interpretive component 5.
Follow up actions (testing, counseling)
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Platform / Test-Specific Considerations?
1. Single-gene disorders - limited and complex
assays - use of arrays (single gene, multiple
mutations) 2. Complex diseases - multiplex
DNA/other assays - use of arrays (several genes
/ metabolites) 3. Quantitative RNA analysis
(diagnosing/staging/grading tumors) 4.
Pharmacogenomics (testing and dosing
implications) 5. Proteomics (i.e., OvaCheck)
(Conrads et al. Endocrine-related cancer(2004)
11163 - www.coriologic.com)
Other issues LIS intra-laboratory referrals,
informed consent confidentiality
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Remember The Big Picture
What is communicated?
What should be communicated?
Diagnostic? Predictive?
Professional Guidance?
Test Order
Health care provider
Genetic counselor
Test Report
(direct to consumer)