Phenotypic Evaluation of Previously Uncharacterized Cytomegalovirus DNA Polymerase Sequence Variants Detected in a Valganciclovir Treatment Trial
Bibliographic record
Abstract
BACKGROUND: In a large randomized trial comparing oral valganciclovir and intravenous ganciclovir for treatment of cytomegalovirus disease in solid organ transplantation, confirmed genotypic drug resistance was uncommon (<5%), but definitive interpretation was limited by the detection of 110 uncharacterized UL54 viral DNA polymerase sequence variants. METHODS: Based on treatment history and genetic locus of the sequence changes, 39 of the sequence variants were prioritized for recombinant phenotyping by construction of cloned viral mutants and drug susceptibility testing in cell culture. RESULTS: Four amino acid substitutions were newly confirmed to alter ganciclovir susceptibility: A505V and I726T conferred a borderline decrease in ganciclovir and cidofovir susceptibility, while Q578L and G841S conferred slightly decreased ganciclovir and foscarnet susceptibility. A nonviable phenotype was found for 8 mutations distributed among amino terminal, exonuclease and catalytic domains. Retesting of stored study specimens could not confirm the original detection of >20 sequence variants, including the nonviable mutations and several resistance mutations. CONCLUSIONS: Newly phenotyped UL54 sequence variants did not significantly change the reported incidence of drug resistance in the clinical trial. Unrecognized sequence variants in diagnostic genotyping reports should be confirmed by additional testing in order to improve clinical decision making.
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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 | 0.007 | 0.008 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| 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".