Abstract
Anti-amyloid therapies and blood-based biomarkers are changing Alzheimer disease workups into a two-stage measurement workflow: screen broadly with cheaper information, then spend scarce confirmatory amyloid measurements where they support the decision that will be reported. Amyloid positron-emission tomography (PET) remains one such protocol measurement for amyloid burden, but PET slots, trial budgets, and payer-facing evidence packages are finite. This paper asks a deliberately operational question: when is simple transparent PET validation enough, and when is a fitted residual-uncertainty score worth the added complexity? For a weighted protocol target, the first-order value of validating subject i is the product of target influence and residual protocol uncertainty. Generic uncertainty sampling uses only the second factor and can spend PET measurements on subjects that are hard to predict but weak for the scientific, clinical, or commercial claim. We apply this rule to the A4/LEARN PET archive, treating observed PET as a design laboratory for scarce-confirmation studies. For the primary APOE4 carrier versus non-carrier contrast in Centiloid 24-or-higher PET positivity, simple APOE4-balanced validation recovers nearly all of the target-specific gain: at PET budget 200, the confidence-interval width ratio relative to random validation is 0.923 for APOE4 balancing and 0.914 for target-specific scoring, while generic uncertainty sampling is 0.980. Other targets behave differently: target-specific scoring gives larger gains for an age-slope analysis and for cutoff-indexed PET positivity. The practical message is simple: spend scarce protocol measurements according to the claim being validated, not only according to prediction uncertainty.
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May 12, 2026cs.CV
Structural MRI-to-amyloid PET synthesis has been proposed as a non-invasive alternative for amyloid assessment in Alzheimer's disease (AD). However, reported performance of identical models varies widely across studies, and increasingly complex architectures have not led to consistent gains. This inconsistency is thought to be caused by a fundamental biological ambiguity: MRI captures neurodegeneration, while PET measures amyloid pathology - two processes that are often temporally decoupled in AD. As a result, similar MRI patterns may correspond to different amyloid states, creating ambiguous one-to-many mappings. MRI-to-amyloid PET synthesis may therefore be intrinsically ill-posed; however, this idea has yet to be tested scientifically. The aim of this work is to test this hypothesis through two controlled experiments. We first control the training distribution by stratifying paired MRI-PET data by amyloid and neurodegeneration status. Using two standard synthesis models under a controlled design, we show that biologically unambiguous mappings are learnable in isolation, but performance collapses when data ambiguity is introduced. This demonstrates that ambiguity in the data distribution, rather than architectural capacity, constrains performance. Second, we show that introducing orthogonal biological information in the form of plasma biomarkers resolves this ambiguity. When multimodal inputs are incorporated, performance improves and stability is restored. Together, these findings suggest that limited and inconsistent performance in MRI-to-amyloid PET synthesis is explained by intrinsic biological ambiguity, and that stable, meaningful progress requires multimodal integration rather than architectural complexity.
Louise E. G. Baron, Ross Callaghan, David M. Cash +3
Jul 30, 2026cs.LG
Machine learning determines which follow-up measurements biological screens collect. In a six-rule Cell Painting battery, the highest-value rule would re-image 96.01% of the library and had a 97.14% false-activation upper bound, showing why predicted value alone cannot justify replacing a fixed plan. We developed OPAL, a held-out decision test that freezes a rule and judges unnecessary measurement, coverage and value after cost against archive-specific criteria fixed before final evaluation. A development-selected sparse Cell Painting rule had 18.2-fold lower added-well burden, but its false-discovery bound exceeded 35%, so the fixed plan remained. LINCS--LJP favored broad acquisition under point-estimate criteria set during development, not selective saving. CTRP required fallback because its frozen score missed measured opportunity. OPAL separates optimization from evidence sufficient to change an experiment.
Jia Bi, Samuel Pinilla, Chenyang Zhu
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