Essay Q's Flashcards
After a successful business case, you have been provided funding to implement a new
test into your laboratory. Using a defined example of a test, describe the quality
management process that you would undertake to bring this test into a routine clinical
service.
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How might you evaluate the cost effectiveness of whole exome or genome
analysis in clinical practice? Why might you want to do undertake such an
evaluation and what would be the challenges?
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You have been asked by your local Haematologists to give a presentation on
current haemato-oncology genetic testing and what will impact on service
provision over the next 5 years. Include current and future testing strategies,
including the techniques, their advantages and disadvantages.
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Compare and contrast with examples the following FOUR approaches for genetic
diagnosis of inherited rare genetic disorders:
(i) whole genome sequencing
(ii) whole exome sequencing
(iii) clinical exome sequencing
(iv) next generation sequencing of a targeted panel of genes.
Include the advantages and disadvantages of each approach.
What is the expected impact on service provision for genetic diagnosis of inherited rare
genetic disorders over the next 5 years?
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Describe with examples the ways in which the utility of a genetic diagnostic test may be
assessed. What processes may be implemented to evaluate test performance and use.
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Describe the theory and application of a method belonging to “Next Generation
Sequencing” (NGS).
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Analysis of tumours for mismatch repair deficiency detects cases with absent mismatch repair
protein expression and/or microsatellite instability but no evidence of a germline mutation.
Describe the possible explanations for this, how these may be investigated and the clinical
relevance.
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What are the drivers towards integration of pathology genetic services? What are
the opportunities and challenges posed by this model?
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A sample sent in for genetic testing has been identified via analysis to be of a
different gender than that reported on the referral card. Describe the procedure
you would follow to investigate this, giving both scientific and technical reasons
that could explain the discrepancy, considering both molecular and cytogenetic
causes.
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What is the definition of stratified medicine? Use specific examples of conditions
where cytogenetic and/or molecular genetic findings are clinically relevant to
stratified medicine.
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Your pathology department has been designated as an Essential Services
Laboratory/Local Genetics Laboratory (spoke laboratory) and all specialised testing
(approximately 50% of the current workload) will be carried out at the Core/Hub
laboratory (Genomics Laboratory Hub (GLH)) which is situated at the University
Teaching hospital in a city 50 miles distant. Discuss the factors to consider in order to
continue providing an excellent service for the local population.
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Core quality metrics for pre-analytical and next generation sequencing analysis (NGS)
stages are crucial to ensure the quality of the data for final variant interpretation.
Briefly describe the methods used and quality metrics at the pre-analytical stage, raw
data and alignment stages and explain why they are important.
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Describe the clinical and biological basis of either DPYD testing in colorectal cancer or
TPMT testing in childhood acute lymphoblastic leukaemia. What do you think the main
barriers are and what factors should you consider when establishing pharmacogenetic
testing services?
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Genetic/genomic testing is routinely performed to identify and stratify cancer patients
for treatment. In the context of the clinical setting in the UK, for either NSCLC or ALL:
Describe
a) which patients and what type of tumours should be tested;
b) which genes should be tested, their common alterations and diagnostic, prognostic
and therapeutic implications, and acceptable methods for testing; Please also discuss
new and emerging genetic or genomic biomarkers for potential targeted or stratified
treatment, why and how to test them
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One of the biggest advances in oncology is the emergence of immune checkpoint
inhibitors that are currently used to treat various tumour types. Recent clinical trial data
looked at and evaluated several biomarkers to select patients eligible for immune
check point inhibitor therapy.
a) What biomarkers do you have knowledge of and how are they used clinically to
select patients for immune check point inhibitors?
b) Discuss benefits and disadvantages of each of these biomarkers for a molecular
pathology service.
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Review the range of methodologies that are available to clinical laboratories
for the detection of oncogene fusions. For each method given, describe the
underlying principle of detection, provide an example of a clinical application
where the method would be suitable and highlight the relative strengths and
weaknesses of each methodology.
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NGS gene panel testing is increasingly used for routine clinical work-up of
myeloid neoplasms. You have been tasked with the development of an NGS
panel to detect small somatic variants (SNV and indel) for diagnosis,
prognosis and treatment of broad myeloid neoplasm including acute myeloid
leukaemia, myelodysplastic syndrome and myeloproliferative neoplasmas.
Describe your rationale behind the design of the panel. How would you plan to
validate and implement the assay?
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Recent clinical trial data suggests that tumour mutation burden (TMB) is a
predictive biomarker of response to immune check point inhibitors irrespective
of the PD-L1 expression status as tested by immunohistochemistry. Discuss
potential issues around the implementation of TMB in clinical practice and
challenges in the context of non-small cell lung carcinoma molecular testing.
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There are several clinical applications of ctDNA as liquid biopsy: prediction of
prognosis, early diagnosis, monitoring of therapies and therapeutic
stratification on progressive disease. These are all of high clinical interest but
there are challenges regarding the specificity and sensitivity of the current
assays employed to deliver these tests. Please discuss pre-analytical issues
affecting the ctDNA samples in patients with advanced lung cancer
progressing on EGFR TKIs and address this in the context of technologies
used for ctDNA testing with particular emphasis on the benefits and limitations
for delivery in clinical practice.
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Describe how you would validate a new “in-house” locally developed
diagnostic assay. What would you do in the absence of an EQA scheme for
the new diagnostic service?
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Describe two examples of how the molecular monitoring of acquired
resistance / disease relapse, can aid patient management?
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What is epigenetics? Give an example of epigenetics in tumour biology, and
of its clinical diagnostic application. How would you test for an epigenetic
change in routine clinical diagnostics?
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How does the tissue fixation process of FFPE (formalin fixed paraffin
embedded) samples impact on downstream molecular analysis? What
measures can be taken to counteract their impact?
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NICE guidance published in 2017 recommends that all patients with a diagnosis of colorectal cancer should be offered testing to identify tumours with deficient mismatch repair, to guide further sequential testing for Lynch syndrome.
a) Describe the techniques that can be used to detect mismatch repair and the advantages and limitations of each one.
b) Outline a molecular testing pathway for Lynch syndrome testing, considering the factors that need to be taken into account to guide patient management and treatment.
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