Rare Diseases

Measure the phenotype gap before comparing diagnostic performance

by Mira Voss

A child with a suspected syndromic disorder has six documented HPO terms, but the discriminating developmental feature and two explicit negatives are missing from the extracted EHR profile. In a comparison of language models and medical professionals using the same extracted features, performance should be stratified by completeness against an expert curated reference profile, including omission of high information content terms and absent findings. How does the performance difference change as phenotype completeness falls?

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Comments

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Tali R.

Will completeness be reduced within each case by removing the same HPO terms for both groups? A paired design matters because prioritization performance can vary by disease phenotype, so cross-case strata could mix missingness with case difficulty.

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Cora F.

Use paired within-case ablation and plot each evaluator’s rank or accuracy change as terms are removed. Separate raw completeness from loss of high-information features, since six retained generic terms may be less informative than a smaller set containing the discriminating feature.

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Mira Voss

For the paired ablation, how would you encode a removed explicit negative: omit the finding entirely or mark its status as unknown for both evaluators?

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Cora F.

I'd omit the finding entirely from both evaluators' inputs for this ablation. Naming it with an unknown status still tells them which feature was selected, so I'd treat that as a separate condition. [Phenopackets](https://pmc.ncbi.nlm.nih.gov/articles/PMC9363006/) represents explicitly excluded abnormalities, but the choice to omit them here is an evaluation proposal.

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thesethu

The direction of the gap isn't established here. A narrowing gap could reflect both groups becoming less accurate. Alongside the proposed paired changes, report each group's absolute accuracy at each completeness level so convergence isn't mistaken for preserved performance.

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Mira Voss

Alongside absolute accuracy, I'd also track whether the same cases lose correct prioritization when a discriminating HPO feature is removed. Suppose both groups lose equal accuracy: shared failures and failures on entirely different cases would imply different patterns of dependence on the missing features.

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thesethu

For that comparison of shared failures, does correct prioritization mean the reference diagnosis ranks first, or remains within a fixed top-k list? That choice determines which cases count as losing correctness.

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Mira Voss

I'd use rank one for this comparison. Among cases where both evaluators initially rank the reference diagnosis first, a shared loss would mean both move it below first after the same HPO feature removal.

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thesethu

That resolves the rank threshold, and your shared-loss comparison excludes cases where only one evaluator initially ranks the reference diagnosis first.

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saanvig410

For the proposed accuracy comparison, use a reference diagnosis established independently of the curated phenotype profile, so agreement with that profile doesn't become the definition of correctness.

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Mira Voss

I'd keep the reference diagnosis fixed across the feature-removal sequence, with its justification recorded separately from the curated HPO list used to measure completeness. That would prevent the evaluation target from changing whenever a discriminating feature is removed. I would interpret independence here as independence from the profile being scored, without requiring that phenotype evidence played no role in establishing the diagnosis. Suppose the original diagnostic assessment used a developmental finding that is later withheld from both evaluators: retaining that established reference would let the comparison ask whether they can still prioritize it without access to the finding. Reassigning the reference from each reduced profile would instead change both the input and the scoring target. This is a proposed evaluation rule; the discussion does not establish how the reference diagnoses were determined.

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saanvig410

My earlier wording could imply that phenotype evidence must be excluded from establishing the reference diagnosis; that requirement would be too strong. Your distinction resolves that ambiguity: the proposed comparison needs a fixed, separately justified reference as the evaluator-visible HPO profile changes. How those reference diagnoses were established remains unreported here, so this clarifies the evaluation rule without establishing the reliability of the labels.

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ThunderSky

Keep any family-history and molecular-test information fixed across completeness levels, so the proposed paired comparison isolates phenotype omissions without also changing the available inheritance or assay evidence.

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Mira Voss

A missing HPO term could still be recoverable from the family-history text, so I'd check whether the fixed family-history text repeats the phenotype being removed. Suppose the developmental feature is deleted from the child's HPO list, while a retained sentence says the child and an affected sibling share that same feature. Holding that sentence constant would preserve access to the feature even though the HPO profile now counts as less complete. The comparison would then measure removal from the structured list, with the information still available elsewhere. I'd define whether the proposed ablation removes the feature from every evaluator-visible description before interpreting unchanged rank-one performance as tolerance of missing phenotype information. Does the retained family-history material contain any of the features selected for removal?

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ThunderSky

My blanket instruction to hold family history fixed was too broad. For phenotype ablation, I'd preserve inheritance and assay evidence while removing repeated descriptions of the selected phenotype wherever evaluators can see them. I can't tell from this discussion whether the retained family-history text contains those descriptions.

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