User:Chantalburnett/sandbox

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This is place to practice clicking the "edit" button and practice adding references (via the citation button). Please see Help:My_sandbox or contact User_talk:JenOttawa with any questions.

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 * Note: Please use your sandbox to submit assignment # 3 by pasting it below. When uploading your improvements to the article talk page please share your exact proposed edit (not the full assignment 3).


 * Talk Page Template: CARL Medical Editing Initiative/Fall 2019/Talk Page Template

Wikipedia page: Hereditary nonpolyposis colorectal cancer

Assignment #2
Topic: Immunohistochemistry (IHC) testing as a screening tool for hereditary nonpolyposis colorectal cancer

Why: This is a commonly used method to screen for hereditary nonpolyposis colorectal cancer, yet it is entirely missing from the Wikipedia page

Search Terms:


 * “Immunohistochemistry testing lynch syndrome”
 * “Immunohistochemistry testing hereditary nonpolyposis colorectal cancer”
 * Rational : Our SGL tutor for this assignment, Dr. Grin, suggested that the term “Lynch syndrome” is a more appropriate medical term to use. This is the more appropriate and commonly used term in the medical field (as opposed to “hereditary nonpolyposis colorectal cancer”), and it’s the term used in the recently published “Classification of Tumours” textbook by the World Health Organization. In fact, our tutor even suggested that the Wikipedia page title be updated to “Lynch syndrome”

Secondary Source Literature Search Strategy


 * Searched the grey literature using Google Scholar (via Queen’s University library)
 * Searched for systematic reviews from high quality journals using the Cochrane Library
 * Changed the search criteria to only include sources that were published within the past five years (i.e. 2014-present)
 * Scanned abstracts for relevance and author affiliation and/or organizations to evaluate credibility and appropriateness of source
 * Many articles focused on a cancer other than colorectal cancer (e.g. endometrioid cancer, prostate cancer, etc.)
 * Eliminated sources that were too narrowly focused or that did not include colorectal cancer as a main topic (because the term “colorectal” is   in the Wikipedia page title “hereditary nonpolyposis colorectal cancer”)

Selected Source : Snowsill T, Huxley N, Hoyle M, et al. A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome. Health Technology Assessment 2014; 18(58):1-406. doi: 10.3310/hta18580


 * Journal is published by the National Institute for Health Research, which is a reputable and credible organization for health research
 * Article objective: “To evaluate the accuracy and cost-effectiveness of strategies to identify lynch syndrome in newly diagnosed early-onset colorectal cancer patients (aged < 50 years). Cascade testing of relatives is employed in all strategies for individuals in whom lynch syndrome is identified.”
 * Page 5-6 provides details of immunohistochemistry:
 * What it is and how it can be used as a screening tool for lynch syndrome
 * The advantage of immunohistochemistry over other methods
 * Information about its sensitivity as a screening tool
 * The issues with immunohistochemistry

Assignment #3
Proposed changes: Adding the following sentences to the Diagnosis section (after the first paragraph): “Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with HNPCC. While it is not diagnostic of a HNPCC, it can play a role in identifying people who should have germline testing.”

- the short form for immunohistochemistry is IHC (not HCl). - The sentences your propose to add are clear and concise, easy to understand by a non medical person

Rational for changes


 * The Diagnosis section includes the Amsterdam criteria, which is a clinical-based tool (i.e. based on family history) used to identify individuals who should be genetically tested for HNPCC, also known as Lynch syndrome (LS). It says that commercial testing is available.
 * However, Snowsill et al.’s systematic review findings show that the current evidence supports the use of immunohistochemistry (IHC) on tumour tissues as a screening tool for LS (as oppose to commercial genetic tests)
 * IHC identifies four mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2) that are associated with LS. Tissues with negative staining proceed to DNA analysis. IHC testing helps to identify the MMR gene that most likely harbours a germline mutation.
 * In families with an increased probability of MMR gene mutation, IHC can be used as the first step to confirm the presence of a MMR deficiency
 * Family members who fulfil the Amsterdam criteria but without evidence of MMR defects via IHC require less frequent colonoscopic surveillance. This is desirable given that surveillance is time-consuming and expensive.
 * An advantage of IHC over microsatellite instability (MSI) is that abnormal staining of MMR proteins is related to the underlying defect and can therefore direct further genetic testing

Areas of controversy


 * Limitations of HCI:
 * While it’s a well-established technique, it must be performed to an adequate standard
 * Sensitivity is limited by a number of factors (e.g. tissue fixation, the variety and different performance characteristics of primary antibodies)
 * Approximately 15% of sporadic colon cancers lose expression of MLH1 because of hypermethylation of the gene’s promoter. Hence, whereas abnormal expression of MSH2, MSH6 or PMS2 is in itself reasonably good evidence that a tumour was due to LS, loss of MLH1 is itself not


 * However, these are minor issues which are very manageable:
 * Making MMR IHC only available within laboratories accredited to Clinical Pathology Accreditation standards
 * Using other evidence for interpretation of results (e.g. testing for MLH1 promoter methylation)

- These are very true limitations of IHC that you state. Great that you recognize those.

Critique of source


 * The source used is a systematic review of current evidence on the accuracy of LS laboratory tests
 * Journal is published by the National Institute for Health Research, which is a reputable and credible organization for health research
 * Paper was published 5 years ago, covering studies up until 2012 (i.e. relatively recent)
 * Provides very clear description of:
 * Search and review strategy
 * Interventions and comparators
 * Study designs inclusion criteria
 * Databases searched (MEDLINE, EMBASE, Web of Science) (i.e. reproducible description)
 * Data extraction strategy (critically appraised by two reviewers)
 * Critical appraisal strategy:
 *  Internal validity :
 * Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) quality appraisal tool
 * Quality was assessed by one reviewer and judgements were checked by a second. Any disagreement was resolved by discussion, with involvement of a third reviewer as necessary
 *  External validity : Judged according to the ability of a reader to consider the applicability of findings to a particular patient group and service setting


 * Risk of bias (QUADAS-2 results)
 * Studies were of mixed quality, with significant methodological concerns identified for most
 * However, the authors conclude that even though IHC is not the gold standard, it can both play a part in diagnosing LS


 * Balanced/transparent approach
 * Authors identified both advantages and disadvantages from the literature on the IHC technique)
 * Identifies sources of bias in the data (e.g. estimates of MMR genes are subject to bias because they are generally mutations found in families referred to genetics clinics, subject to fulfilment of local referral guidelines)


 *  Overall : while the authors identified some methodological concerns in the selected articles, this does not affect the results as the authors do not state that IHC is a gold standard test, but can still be a useful diagnostic tool when used in conjunction with other tools (e.g. microsatellite instability)

 Citation: