medical-test-reviews-genetic.ppt

Challenges in and Principles for
Conducting Systematic Reviews of
Genetic Tests Used as
Predictive Indicators
Prepared for:
The Agency for Healthcare Research and Quality (AHRQ)
Training Modules for Medical Test Reviews Methods Guide
www.ahrq.gov

Describe challenges in and principles for conducting
systematic reviews of genetic tests used as predictive
indicators.
Recognize the utility of organizing frameworks and
analytic frameworks.
Assess the importance of preanalytic, analytic, and
postanalytic factors used for evaluating genetic tests.
Understand important statistical and bias issues involved
with predictive genetic tests.
Learning Objectives
Jonas DE, Wilt TJ, Taylor BC, et al. Challenges in and principles for conducting systematic reviews of genetic tests used as
predictive indicators. In: Methods guide for medical test reviews. Available at www.effectivehealthcare.ahrq.gov/medtestsguide.cfm.

Background on Genetic Tests
Challenges in Reviews of Genetic Tests
Principles for Addressing the Challenges
Illustrative Examples
General Overview

General Overview: Section 1

 This module focuses on genetic tests that:
1. Determine risk in asymptomatic individuals
 For example, BRCA1/BRCA2 hereditary mutations for breast and
ovarian cancer
2. Reveal prognostic information to guide future clinical
management and treatment in those with a condition
 For example, the Oncotype Dx® test of acquired tumor genome
mutations for breast cancer recurrence
3. Predict response, using hereditary genetic makeup, to
treatments or environmental factors including:
 Diet (nutrigenomics)
 Drugs (pharmacogenomics)
 Infectious agents
 Chemicals
 Physical agents
 Behavioral factors
Background: Genetic Tests (1 of 2)

 Key factors specifically affecting hereditary genetic tests need
to be taken into account. These are:
 Penetrance of the disease
 Variable expressivity
 Pleiotropy
 Time lag to outcomes
 The first three terms (penetrance, variable expressivity, and
pleiotropy) usually refer to single-gene disorders.
 Single-gene disorder: Occurs as the result of a single mutated
gene; is inherited in well-described ways
 Polygenic disorder: Occurs as the result of combined action of
more than one gene; is not inherited in simple Mendelian patterns
Background: Genetic Tests (2 of 2)

Penetrance
Penetrance is the proportion of people with a
particular genetic change who exhibit signs and
symptoms of a disorder.
It is essential in determining the future risk of
developing a disease and for assessing clinical
utility of genetic tests.
Sufficient data may be lacking to estimate
penetrance.
Challenges in Reviews of Genetic Tests (1 of 6)
Lister Hill National Center for Biomedical Communications. Genetics Home Reference: What are reduced penetrance and variable
expressivity. Available at www.ghr.nlm.nih.gov/handbook/inheritance/penetranceexpressivity.

Variable Expressivity
Variable expressivity is the range of severity of
symptoms among different people with the same
condition.
Example: Hemochromatosis manifests into a wide
spectrum of symptoms that vary in severity from
mild to life threatening.
The degree of expressivity should be considered in
evaluating genetic tests.
Lister Hill National Center for Biomedical Communications. Genetics Home Reference: What are reduced penetrance and variable
expressivity. Available at www.ghr.nlm.nih.gov/handbook/inheritance/penetranceexpressivity.

Pleiotropy
This term refers to a single gene’s influence on
multiple phenotypic traits.
For example, the genetic mutation causing
Marfan’s syndrome results in cardiovascular,
skeletal, and ophthalmologic abnormalities.
BRCA1 and BRCA2 mutations can influence the risk
for multiple cancer types including breast, ovarian,
prostate, and skin (i.e., melanoma).

Time Lag
This term refers to the time difference between
genetic testing and clinically important events.
Sufficient duration of studies is important in
evaluating studies of genetic tests.
It should be determined if subjects have reached
the age beyond which clinical expression would be
likely.

Other Challenges
 Direct evidence for the impact of genetic test results on
health outcomes is often lacking.
 The evidence base is too limited in scope.
 It is difficult to find published information on various aspects of
genetic tests, particularly analytic validity.
 There are several technical issues that are relevant to
assessment of analytic validity. These issues:
 Differ according to the type of test
 May influence interpretation of results
 May differ, depending on the specimen being tested (e.g.,
different considerations when assessing tumor genomes vs.
human genomes)

Other Challenges (Continued)
 Difficulties can arise when determining susceptibility
or risk in asymptomatic individuals.
 Utility of a test may depend on the ability of individuals
to report and identify certain clinical factors.
Statistical issues must also be taken into account.
Genetic test results often are derived from analytically
complex studies that have undergone a very large
number of statistical tests.

1. Use an organizing framework appropriate for genetic tests.
2. Develop analytic frameworks to reflect the predictive nature of
genetic tests and incorporate appropriate outcomes.
3. Search databases appropriate for genetic tests.
4. Consult with experts to determine which technical issues are
important to address in assessing genetic tests.
5. Distinguish between functional assays and DNA-based assays to
determine important technical issues.
6. Evaluate case-control studies carefully for potential selection bias.
7. Determine the added value of the genetic test over existing risk
assessment approaches.
8. Understand statistical issues of particular relevance to genetic tests.
Principles for Addressing the Challenges

 Organizing frameworks for genetic tests have been developed by the
USPSTF, the CDC, and the EGAPP Working Group.
 The ACCE model is endorsed by the EGAPP Working Group. The
criteria of the model are as follows:
1. Analytic validity (technical accuracy and reliability)
2. Clinical validity (ability to detect or predict an outcome, disorder, or
phenotype)
3. Clinical utility (whether test ultimately leads to improved patient
outcomes)
4. Ethical, legal, and social implications
 The ACCE model has also developed a series of 44 questions
following these criteria.
 The questions help define a review’s scope and critically appraise
studies.
Principle 1: Use an Organizing Framework
Appropriate for Genetic Tests

ACCE Model Questions for Reviews of Genetic Tests
(1 of 3)
Element Questions
Disorder/
setting
1. What is the specific clinical disorder to be studied?
2. What are the clinical findings defining this disorder?
3. What is the clinical setting in which the test is to be performed?
4. What DNA test(s) are associated with this disorder?*
5. Are preliminary screening questions employed?
6. Is it a stand-alone test or is it one of a series of tests?
7. If it is part of a series of screening tests, are all tests performed in all instances
(parallel) or are only some tests performed on the basis of other results (series)?
Analytic
validity
8. Is the test qualitative or quantitative?
9. How often is the test positive when a mutation is present?*
10. How often is the test negative when a mutation is not present?*
11. Is an internal quality control program defined and externally monitored?
12. Have repeated measurements been made on specimens?
13. What is the within-and between-laboratory precision?
14. If appropriate, how is confirmatory testing performed to resolve false positive
results in a timely manner?
15. What range of patient specimens have been tested?
16. How often does the test fail to give a usable result?
17. How similar are results obtained in multiple laboratories using the same, or
different technology?

(2 of 3)
Clinical
validity
18. How often is the test positive when the disorder is present?
19. How often is the test negative when a disorder is not present?
20. Are there methods to resolve clinical false positive results in a timely
manner?
21. What is the prevalence of the disorder in this setting?
22. Has the test been adequately validated on all populations to which it may
be offered?
23. What are the positive and negative predictive values?
24. What are the genotype/phenotype relationships?*
25. What are the genetic, environmental or other modifiers?*
Clinical
utility
(Continued)
26. What is the natural history of the disorder?
27. What is the impact of a positive (or negative) test on patient care?
28. If applicable, are medical tests available?
29. Is there an effective remedy, acceptable action, or other measurable benefit?
30. Is there general access to that remedy or action?
31. Is the test being offered to a socially vulnerable population?
32. What quality assurance measures are in place?
33. What are the results of pilot trials?
34. What health risks can be identified for follow-up testing and/or
intervention?

(3 of 3)
Clinical
utility
(Continued)
35. What are the financial costs associated with testing?
36. What are the economic benefits associated with actions resulting from testing?
37. What facilities/personnel are available or easily put in place?
38. What educational materials have been developed and validated and which of
these are available?*
39. Are there informed consent requirements?*
40. What methods exist for long term monitoring?
41. What guidelines have been developed for evaluating program performance?
Ethical,
legal, and
social
implications
42. What is known about stigmatization, discrimination, privacy/confidentiality and
personal/family social issues?*
43. Are there legal issues regarding consent, ownership of data and/or samples,
patents, licensing, proprietary testing, obligation to disclose, or reporting
requirements?*
44. What safeguards have been described and are these safeguards in place and
effective?*

 Clearly define the Key Questions and understand the needs of
decisionmakers and the test context.
 Consider whether test is used to:
 Determine the future risk of disease in asymptomatic individuals
 Establish prognostic information that will influence treatment
decisions
 Predict response to treatments (either effectiveness or harms)
 Clarify the specimens (e.g., patient or tumor genome) to be
tested.
 Clearly describe the PICOTS typology.
 Doing so will inform development of the analytic framework and
vice versa.
Principle 2: Develop Analytic Frameworks To Reflect the
Predictive Nature of Genetic Tests and Incorporate
Appropriate Outcomes (1 of 5)

A Generic Analytic Framework for Evaluating Predictive Genetic Tests
 Considering preanalytic, analytic, and postanalytic factors, as
well as outcomes, in analytic frameworks may be useful.

The adverse effects of genetic testing are:
 Potential effects on family members
 Psychological distress
 Potential stigmatization or discrimination
Harms particularly occur with the prediction of high disease
probability, but no preventative or ameliorative measures
exist.
For these harms, take into account:
 Whether testing is for inherited or acquired mutations/
variations
 Whether the test condition is multifactorial or follows
Mendelian inheritance patterns

Other outcomes include but are not limited to:
 Cost
 Quality of life
 Long-term morbidity
 Indirect impact
Genetic tests may impact decisions that are difficult to
measure yet are very important (e.g., decisions regarding
pregnancy).
The impact of genetic testing on family members may be
important depending on context
 Particularly in cases involving testing for heritable conditions

Generic Analytic Framework for Evaluating Predictive Genetic
Tests When the Impact on Family Members Is Important

 Human Genome Epidemiology Network (HuGE Net)
 HuGE Net is a good supplement to main literature databases (e.g.,
PubMed®).
 It contains meta-analyses of genetic association studies.
 The HuGE Navigator can identify all types of available studies related to
a genetic test.
 Gray Literature
 Package inserts for genetic tests approved by the U.S. Food and Drug
Administration (FDA)
 These inserts include summaries of analytic validity data that were
instrumental during FDA approval.
 They are available on the FDA Web site and on that of the test manufacturers.
 Genetic test data are also available from the FDA Center for Devices and
Radiological Health Web site.
Principle 3: Search Databases Appropriate for
Genetic Tests (1 of 2)

 Gray Literature (Continued)
 American College of Medical Genetics and College of American
Pathologists joint external proficiency testing program
 Useful when no published data on analytic validity exist
 Gives degree of lab-to-lab variability and sense of reproducibility
 Professional society conference publications
 GeneTests Web site sponsored by the Genetic Alliance
 Association for Molecular Pathology Web site
 Centers for Disease Control and Prevention programs (e.g., the Genetic
Testing Reference Materials Coordination Program)
 International proficiency testing programs
 LexisNexis® database and Cambridge Healthtech Institute
 Use to identify genetic tests in development for cancer
Principle 3: Search Databases Appropriate for
Genetic Tests (2 of 2)

Consult with an expert familiar with a genetic test to
determine which of the following technical issues are
pertinent:
 Preanalytic Factors
 Obtaining, preserving, and storing samples before analysis
 Analytic Factors
 Type of assay, sample, methods being used, et cetera
 Postanalytic Factors
 Complexity of interpreting the genetic test result, lab-to-lab
variability, and quality control
Principle 4: Consult With Experts To Determine Which
Technical Issues Are Important in Assessing Genetic Tests

Questions for Assessing Preanalytic, Analytic, and
Postanalytic Factors for Evaluating Predictive Genetic Tests
Element Questions*
Preanalytic • What patient characteristics are relevant to the analytic validity of the test (e.g., age, sex,
ethnicity, race, ancestry, parental history of consanguinity, family health history)?
• What types of samples were used?
• How were samples obtained?
• How were samples handled and stored prior to analysis?
Analytic • What type of assay was used? What is the reliability of the assay?
• What specific analyte was investigated (e.g., specification of which alleles, genes, or
biochemical analytes were evaluated)?
• For DNA-based tests, what is the definition of the genotype investigated?
• Did the study test for all potentially relevant alleles?
• For DNA-based tests, what genotyping methods were used?
• When were samples analyzed (compared to when they were collected)?
• Was the timing of analysis equal for both study groups (if applicable)?
• How often does the test give a usable result (what is the “call rate”)?
Postanalytic • How are the test results interpreted and applied? How complex is interpretation and
application?
• What quality control measures were used? Were repeated measurements made on specimens?
• How reproducible is the test over time? How reproducible is the test when repeated in the
same patient multiple times? How reproducible is the test from laboratory to laboratory?
*Portions of this table were adapted from Burke et al. (2002) and Little et al. (2002).
Burke W, Atkins D, Gwinn M, et al. Am J Epidemiol 2002 Aug 15;156(4):300-10. PMID: 12181100.
Little J, Bradley L, Bray MS, et al. Am J Epidemiol 2002 Aug 15;156(4):300-10. PMID: 12181099.

Functional Assays
 Are used to measure the substrate/metabolic product
affected by a genetic polymorphism
 Have the advantage of showing functional significance of an
underlying genetic polymorphism
 Can be affected by factors unrelated to a polymorphism:
 Unmeasured environmental factors
 Other genetic polymorphisms
 Various disease states
 Assays that measure enzyme activity:
 Are evaluated at a single point in time
 Yield activities that vary over time
Principle 5: Distinguish Between Functional Assays and DNA-
Based Assays To Determine Important Technical Issues (1 of 3)

DNA-Based Assays
Analyze the DNA itself
Use a variety of sample sources (e.g., blood, cheek
swab, hair)
 All samples should result in identical genotypic results.
 Some sources more difficult to isolate DNA from (e.g.,
formalin-fixed tissue).
Studies sometimes use different sources of DNA, which
can introduce measurement bias because of
differences in ease of technique and test accuracy.

Extracting DNA from tumor samples raises additional
issues:
 Quantity of tissue
 Admixture of normal and cancerous tissue
 Amount of necrosis
 Timing of collection
 Storage technique (e.g., fresh, frozen, paraffin, formalin)
Complexity of test method, lab-to-lab variability, and
quality control should be evaluated.

It is essential for cases and controls to be selected from
the same source population.
Matching cases and controls for ethnicity/race is
preferred over stating the geographic location of a
source population.
 This is because frequencies of DNA polymorphisms vary
from population to population.
Generally, only nested case-control studies have a
potential for selection bias that is low enough to provide
reliable information.
Principle 6: Evaluate Case-Control Studies
Carefully for Potential Selection Bias

Many clinical factors associated with risk assessment may
already be well characterized.
Reviewers should assess the added value of using genetic
testing along with known factors when compared with
using known factors alone.
 Example: Cardiovascular Disease
 Age, sex, smoking, hypertension, diabetes, and cholesterol are
known risk factors.
 Assessment of newly identified polymorphisms (such as on
chromosome 9p21) should be evaluated in context with these
known factors to determine added value.
Principle 7: Determine the Added Value of the Genetic
Test Over Existing Risk Assessment Approaches

Hardy-Weinberg Equilibrium (HWE)
 Most allele distributions follow a usual distribution, the
HWE.
 Distributions deviate from HWE due to:
 New mutations
 Selection
 Migration
 Genetic drift
 Inbreeding
 Chance (applies when many polymorphisms are tested)
Principle 8: Understand Statistical Issues of
Particular Relevance to Genetic Tests (1 of 4)
Attia J, Ioannidis JP, Thakkinstian A, et al. JAMA 2009 Jan 7;301(1):74-81. PMID: 19126812.
Attia J, Ioannidis JP, Thakkinstian A, et al. JAMA 2009 Jan 14;301(2):191-7. PMID: 19141767.

Sample Size Calculations
It is important to assess whether sample size
calculations appropriately accounted for:
The number of variant alleles
The prevalence of variants in the study population
Pharmacogenomic studies often enroll an
insufficient number of subjects to account for
these factors.
Williams JA, Johnson K, Paulauskis J, et al. J Clin Pharmacol 2006 Mar;46(3):258-64. PMID: 16490801.

Genetic Association Studies
 Genetic test results are sometimes derived from complex
studies with a large number of statistical tests.
 For example, genome-wide association studies that search for
associations between a huge number of genetic
polymorphisms and health conditions
 These studies should generally be regarded as hypothesis
generating rather than hypothesis testing or confirmatory
of cause-effect relationships.
 Associations should be validated in multiple studies to
minimize potential confounding and publication bias.
 Evaluating causality may be difficult because of factors
that influence associations (e.g., environmental exposures,
behaviors, other genes).

 Overlapping Data Sets
 Publications may sometimes have overlapping data sets regarding
prevalence of genetic variants.
 Genome-wide association studies or other large collaborative efforts
may pool patients who were previously included in other published
studies.
 To the extent possible, double-counting should be avoided by
investigators.
Assessing Tumor Genetics
 Tumor genomes may be in a dynamic state.
 Tumor specimens often contain normal patient cells.
 Specimen characteristics affect the operation and sensitivity of
the test.

 Adults with depression who are treated with selective
serotonin reuptake inhibitors (SSRIs) undergo genetic testing
for cytochrome P450 polymorphisms.
 This is an example of a well-defined predictive genetic testing
scenario.
 The investigators developed an analytic framework and five key
questions to explore the chain of evidence leading to
intermediate outcomes.
 The investigators found no prospective studies of the use of
genotyping to guide treatment that measured clinical outcomes
 The investigators evaluated the links between genotype and
metabolism of SSRIs (phenotype), metabolism and SSRI efficacy,
and metabolism and adverse drug reactions to SSRIs.
Illustrative Example 1:
Cytochrome P450 Testing (1 of 2)
Matchar DB, Thakur MD, Grossman I, et al. Evidence Report/Technology Assessment No. 146. Available at
www.archive.ahrq.gov/downloads/pub/evidence/pdf/cyp450/cyp450.pdf.

Analytic Framework for Gathering Evidence on CYP450 Genotyping
of Adults Receiving SSRI Treatment for Nonpsychotic Depression
Cytochrome P450 Testing (2 of 2)
*The circled numbers refer to the Key Questions addressed.
SSRI = selective serotonin reuptake inhibitors
*
Matchar DB, Thakur MD, Grossman I, et al. Evidence Report/Technology Assessment No. 146. Available at
www.archive.ahrq.gov/downloads/pub/evidence/pdf/cyp450/cyp450.pdf.

 Assessment of human epidermal growth factor receptor 2
(HER2) status is used to manage patients with breast cancer
and other solid tumors.
 HER2 testing is challenging because of substantial heterogeneity
and the lack of information related to test methods.
 Very recently, certain aspects of the HER2 test were standardized.
 Before standardization, the effects of widely varying test methods
could not be isolated.
 The challenges of HER2 testing were targeted in narrative review
with this Key Question:
What is the evidence of concordance and discrepancy rates for methods
(e.g., fluorescence in situ hybridization, immunohistochemistry, etc.)
used to analyze HER2 status in breast tumor tissue?
Illustrative Example 2: HER2 Testing
Seidenfeld J, Samson DJ, Rothenberg BM, et al. Evidence Report/Technology Assessment No. 172. Available at
www.ahrq.gov/research/findings/evidence-based-reports/her2-evidence-report.pdf

 Testing for the BRCA mutation is used to predict risk of breast and ovarian
cancer in high-risk women.
 The need for such testing exemplifies the importance of obtaining an
accurate family history.
 Population-based BRCA testing is currently not appropriate.
 All contributing genes are not known.
 Mutation detection methods are not perfect.
 Family history is used to determine risk categories instead.
 It is the key preanalytic factor with influence on analytic validity.
 Family history is a genetic/genomics tool used to:
 Identify people with possible inherited susceptibilities
 Guide genetic testing
 Help interpret genetic test results
 Assess disease risk
BRCA Mutation Testing (1 of 2)
Nelson HD, Huffman LH, Fu R, et al. Ann Intern Med 2005 Sep 6;143(5):362-79. PMID: 16144895.
U.S. Preventive Services Task Force. Ann Intern Med 2005 Sep 6;143(5):355-61. PMID: 16144894.

 The ability of providers to accurately determine a family
history that indicates increased risk is needed for BRCA
mutation tests and other predictive genetic tests to be
useful.
 Sometimes it is difficult for people to accurately recall
whether their relatives have a medical condition.
 The sensitivity and specificity of family history self-reports
are important in determining overall usefulness of
predictive genetic testing.
BRCA Mutation Testing (2 of 2)
Nelson HD, Huffman LH, Fu R, et al. Ann Intern Med 2005 Sep 6;143(5):362-79. PMID: 16144895.

 The general principles for evaluating genetic tests are similar to
prognostic or predictive tests, but differences exist in their
application and relevance.
 A clearly defined clinical scenario and analytic framework are
important for evaluating any test.
 Organizing frameworks—such as the ACCE model (analytic validity,
clinical validity, clinical utility, and ethical, legal, and social
implications)—and analytic frameworks are useful for evaluating
genetic tests.
 Preanalytic, analytic, and postanalytic factors should be considered
when constructing an analytic framework.
 Predictive genetic tests generally have a time lag between testing
and clinically important events.
Key Messages (1 of 2)

Published information on the analytic validity of genetic
tests may be difficult to locate—Web sites and gray
literature may be important sources.
When clinical factors associated with risk are well
known, genetic tests should be evaluated for added
value.
For genome-wide association studies, it should be
determined whether the association has been validated
in multiple studies to minimize confounding and
publication bias and whether appropriate adjustments
for multiple comparisons were used.
Key Messages (2 of 2)

1. Reviewers should assess the added value of using
genetic testing along with which of the following:
i. Known risk factors
ii. Age, sex, hypertension, etc.
iii. Functional assays
Choices:
a. i only
b. i and ii
c. i and iii
d. i, ii, and iii
Practice Question 1 (1 of 2)

Explanation for Question 1:
The correct answer is b. Reviewers should assess the added
value of using genetic testing technology along with known
risk factors. Age, sex, and hypertension are examples of
known risk factors that may apply to the disease being
studied, and genetic tests should be evaluated in context
with known risk factors such as these.

2. Analytic frameworks for evaluating predictive genetic
tests only focus on the preanalytic, analytic, and
postanalytic factors that affect the test.
a. True
b. False

The statement is false. Analytic frameworks for evaluating
predictive genetic tests do include considerations of
preanalytic, analytic, and postanalytic factors; however,
other factors are also included, such as outcomes, benefits,
harms, and the intended use of the test.

3. The “E” in the ACCE model refers to which of the
following:
a. Expressivity
b. Effectiveness
c. Efficacy
d. Ethical
e. Environmental

The correct answer is d. The “E” stands for ethical. ACCE is
an acronym for analytic validity, clinical validity, clinical
utility, and ethical, legal, and social implications.

This presentation was prepared by Brooke Heidenfelder,
Rachael Posey, Lorraine Sease, Remy Coeytaux, Gillian
Sanders, and Alex Vaz, members of the Duke University
Evidence-based Practice Center.
The module is based on Jonas DE, Wilt TJ, Taylor BC, et
al. Challenges in and principles for conducting systematic
reviews of genetic tests used as predictive indicators. In:
Chang SM and Matchar DB, eds. Methods guide for
medical test reviews. Rockville, MD: Agency for
Healthcare Research and Quality; June 2012. p. 11.1-17.
AHRQ Publication No. 12-EHC017. Available at
www.effectivehealthcare.ahrq.gov/medtestsguide.cfm.
Authors

 Attia J, Ioannidis JP, Thakkinstian A, et al. How to use an article
about genetic association: A: Background concepts. JAMA 2009 Jan
7;301(1):74-81. PMID: 19126812.
 Attia J, Ioannidis JP, Thakkinstian A, et al. How to use an article
about genetic association: B: Are the results of the study valid? JAMA
2009 Jan 14;301(2):191-7. PMID: 19141767.
 Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene
variants and congenital anomalies: a HuGE review. Am J Epidemiol
2000 May 1;151(9):862-77. PMID: 10791559.
 Brockton N, Little J, Sharp L, et al. N-acetyltransferase
polymorphisms and colorectal cancer: a HuGE review. Am J
Epidemiol 2000 May 1;151(9):846-61. PMID: 10791558.
 Burke W, Atkins D, Gwinn M, et al. Genetic test evaluation:
information needs of clinicians, policy makers, and the public. Am J
Epidemiol 2002 Aug 15;156(4):311-8. PMID: 12181100.
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