Gaps in the phenotype descriptions of ultra-rare genetic conditions: review and multicenter consensus reporting guidelines
Bibliographic record
Abstract
ABSTRACT Background Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-first ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. Methods We identified reports published from 2017-2021 in ten genetics journals of novel Mendelian disorders ascertained genotype-first. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. Results In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the six domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n=95) rarely addressed the limitations of the original reports. Reporting guidelines were developed for each domain. Conclusion Phenotype information relevant to clinical management, genetic counseling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. Use of the proposed guidelines could improve phenotype reporting in the genomic era.
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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 | 0.319 | 0.523 |
| Meta-epidemiology (narrow) | 0.003 | 0.003 |
| Meta-epidemiology (broad) | 0.009 | 0.010 |
| Bibliometrics | 0.046 | 0.025 |
| Science and technology studies | 0.003 | 0.006 |
| Scholarly communication | 0.011 | 0.013 |
| Open science | 0.012 | 0.014 |
| Research integrity | 0.008 | 0.005 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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; the direct Gemma label and the distilled Codex classifier agree on what is shown here.
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".