Understanding the impact of uncertain mismatch repair-deficient results for individuals undergoing screening for Lynch syndrome
Bibliographic record
Abstract
Background: In Manitoba, patients diagnosed with colorectal (CRC) or endometrial cancer are screened for Lynch syndrome (LS) using mismatch repair immunohistochemistry (MMR-IHC). In a number of screen positive cases (deficient MMR or dMMR), however, a pathogenic variant associated with LS cannot be identified. The implications of dMMR results are uncertain, as LS cannot be confirmed or ruled out and few guidelines are available regarding interpretation and clinical management. Assessment of the impact of these results on clinicians and patients is needed. We aimed to describe the characteristics of the Manitoba cohort of patients with these uncertain results and how these results have affected individuals. Methods: This study employed a mixed-methods parallel convergent design. Electronic records were searched for patients with dMMR results who were seen in the Shared Health Program of Genetics and Metabolism between 2013 and May 2022. Data extracted from charts included demographics, cancer diagnoses, mode of ascertainment, genetic test results, pedigree review and classification, and details from clinic letters. Qualitative interviews with a subset of patients were conducted to explore experiences with these results. Results: Two-thirds of the cohort (n = 124) were ascertained through the provincial LS screening program. 59.5% did not meet family history criteria for LS, and 50.4% would not have otherwise been eligible for genetic testing based on the Prediction Model for Gene Mutations (PREMM5). Only 25.9% of patients who had a personal and/or family history of CRC received colonoscopy recommendations for themselves, while 89.6% received advice for relatives. Four categories describing experiences with receiving genetic testing results were identified through individual interviews: experiences with testing, varying interpretations, future cancer risk perception, and important elements of a genetic counselling appointment. Participants interpreted their results in one of three ways, leading to different perceptions of future cancer risk. There was consistency between participants’ interpretations of results and how results were communicated to them. Conclusions: Patients with unexplained dMMR have varying interpretations of their genetic test results, leading to ongoing concerns about LS. Traditional family history criteria may be useful post-testing. Personal and/or family history of CRC may guide more consistent colonoscopy recommendations.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.009 | 0.040 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.002 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".