Subtle structural abnormalities in genotype positive phenotype ‘negative’ patients with pre-clinical hypertrophic cardiomyopathy (HCM): a blinded, controlled cardiovascular magnetic resonance (CMR) study
Bibliographic record
Abstract
Mutation carriers without hypertrophy - gene positive, phenotype negative (G+P-) - are not uncommon in clinical practice. There is debate about the presence of subtle abnormalities or variants of the left ventricle in G+P- individuals. Previous research into this area only evaluated limited mutations in the myosin binding protein C and α-tropomyosin genes. We hypothesized: 1) that G+P- patients with pathogenic or presumed pathogenic (PA/PP mutations) have subtle abnormalities of LV morphology recognisable by CMR in pre-clinical HCM but absent in a control population; and 2) that these signs are also present in gene negative patients with a normal wall thickness (G-P-) but high clinical probability of HCM (based on assessment of clinical or family history, electrocardiographic or echocardiographic criteria). The study population had 3 groups - Group 1 (G+P-, tested positive for PA/ PP mutations, n=18); Group 2 (G-P-, Under evaluation for HCM, tested negative for [PA/ PP] mutations, n=20); and Group 3 (controls, n=36). Two experienced CMR readers (blinded to results of genetic testing and clinical context) scored each case for probability of the case representing HCM based on pre-defined signs at CMR including the presence/absence of: a) deep basal inferoseptal crypts (DBISC); b) sudden wall thickness change by >50% in adjacent segments (SWTC); c) inappropriate wall thinning (IWT); d) apical-basal false tendon (ABFT); e) lack of apical tapering (LAT); f) snub nose apical contour (SNAC) . Cases were reviewed individually and in consensus. An experienced HCM cardiologist (blinded to CMR findings) reviewed clinical data, electrocardiograms and echocardiograms and scored each case for likelihood of HCM. Of the 18 G+P- patients, 78% had DBISC, 67% had an ABFT, 50% had IWT and 39% had SWTC. DBISC were seen in cases with PA/PP MYBPC3, TPM1, TNNT2 and MYH7 mutations. All G+P- cases had at least one subtle sign. All G-P- cases classified clinically as high probability of HCM, were classified as high probability of HCM on imaging grounds and had 2 or more subtle signs of HCM: DBISC, SWTC, IWT, ABFT, SNAC and LAT. Controls had no DBISC, SWTC, IWT or LAT. Subtle structural abnormalities visible on CMR help identify PA/PP sarcomeric mutation carriers, as well as G- P- with high clinical probability of HCM, in a genetically heterogenous population.
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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 | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".