Held-out evidence resolves follow-up measurement decisions in biological screens

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.

Systems that automate scientific discovery must repeatedly decide which experiment to run, which hypothesis to test, which tool to build, and when to stop. Many systems make these decisions by maximizing a myopic score such as expected information gain per unit cost or a learned plausibility score. We identify a structural limitation of this approach. Some actions are constructive: they acquire an epistemic capability (an instrument, assay, pipeline, simulator, or abstraction) whose value lies not in the information returned immediately but in the future actions it makes available. When the least-cost route to a confident answer requires a chain of such constructions, a planner that scores actions only by information obtainable within a bounded horizon cannot value the first construction: it yields no information within the horizon and is dominated by any measurement with positive information, however small. We formulate goal-directed discovery as a stochastic shortest-path problem in belief space in which constructive experiments change the downstream action graph, and prove that for every lookahead depth d there is an instance on which every myopic information-maximizing planner has an unbounded approximation ratio, and a related instance on which it never reaches the goal. The mechanism is a capability-indistinguishability lemma: within the horizon, acquiring a capability can be observationally indistinguishable from paying for a null action. This establishes capability gating as a reachability axis of difficulty distinct from curvature (submodularity) and information order (adaptivity gaps). We introduce CG-Plan, an incremental replanner with a capability-aware cost-to-go heuristic h = h_cap + h_exp. In a controlled testbed, the performance gap appears only under gating, persists for every fixed horizon, and arises when near-miss hypotheses come from a data-consistent proposer.

Suppose a planner has a pre-trained simulator of a sequential decision problem and the option to run real experiments in the field. The simulator is cheap to query but inherits confounding and drift from its calibration data. Experimentation is unbiased but consumes one real unit per trial. We study when, and how, the planner should supplement the simulator with experiments. We give three results. First, an extended simulation lemma decomposes the simulator's value error into a calibration--deployment shift that randomization can identify and a parametric residual that no further interaction can reduce. Second, the value gap between the simulator-optimal policy and the optimum splits into a local component, on states the deployed policy already visits, and a reachability component, on states it does not. The reachability component stays bounded away from zero at any horizon under purely passive learning. Third, we propose Fisher-SEP, a simulation-aided experimental policy (SEP) that minimizes the posterior predictive variance of a target policy's value, with reward-only and transition-only specializations. Two case studies illustrate the regimes. In a vending-machine supply chain, front-loaded experimentation overtakes posterior updating once the horizon is long enough to amortize the pilot. In an HIV mobile-testing example with a corridor that separates a well-surveilled region from a poorly-surveilled one, only designed exploration reaches the poorly-surveilled region.