clinical trial designers

Abstract: Prioritizing central nervous system (CNS) interventions requires predicting how a dose, route, and schedule act on a partially observed microenvironment, then choosing the measurement that would change the decision. Action-conditioned predictors reduce a regimen to an identity token or a scalar exposure, discarding where and when the target is engaged; handing a point estimate to a separate planner then discards the joint uncertainty that makes a measurement worth running. We therefore treat decision quality as a property of the intervention interface, not of controller placement. NeuronSifter compiles regimens into state-conditional target-occupancy fields with support masks, propagates them through microenvironment dynamics with an occupancy-conditioned diffusion operator, and selects measurements by their expected reduction in intervention loss, assimilating typed outcomes into the same posterior. In a declared synthetic Alzheimer's disease (AD) evaluation over 64 paired scenario blocks, occupancy conditioning lowers trajectory continuous ranked probability score from 0.165 to 0.110 and raises intervention ordering accuracy from 0.760 to 0.880, and every paired benchmark contrast remains separated after Holm correction. Decision-directed acquisition attains terminal risk 0.160 against 0.166 for a matched numerical Bayesian experimental design planner, and reaches the target risk at 0.796 $[0.732,0.873]$ of an earlier design control's cost, while the corresponding ratio against the matched planner, 0.963 $[0.907,1.025]$, is not separated from equality; point-state and dependence-ablated interfaces instead raise risk to 0.220 and 0.199, and a full-posterior external controller ties exactly. Published AD trials supply a separate retrospective endpoint bridge.

Abstract: We develop an index policy for finite-horizon Bernoulli multi-armed bandits from minimax solutions to single-arm bandit (SAB) problems. Each SAB problem involves choosing between an unknown Bernoulli arm and a known reward. We show that minimizing worst-case regret of SAB problems over all non-anticipative policies admits an exact semi-infinite linear programming formulation. The resulting stopping policies offer a natural way to compare arms: the higher the known reward against which a policy continues sampling, the more promising the unknown arm. We turn this intuition into indices based on cumulative continuation probabilities, with a monotone adjustment and a reward-shortfall cap. By relating index errors to the regret of single-arm stopping policies, we establish a distribution-free regret bound of $4.45\sqrt{KT}+10.75K$ for $K$ arms and horizon $T$. This bound matches the minimax-optimal regret order established in the literature. The guarantee extends to rewards supported on $[0,1]$ through Bernoulli randomization. We also provide a finite-grid implementation with quantified approximation loss. In numerical experiments, the SAB-based index policy achieves lower worst-case regret than every tested benchmark policy across all evaluated numbers of arms and horizons, while closely matching the grid-based MAB minimax policy in the two-arm setting.

Abstract: AI-generated covariates from notes, conversations, images, and wearable streams can change the causal question when their roles are left unspecified. A generated feature may represent a treatment version, pre-action state, history, design variable, mediator, outcome proxy, observation process, or intercurrent event; these roles are not interchangeable. We formulate a causal type discipline for sequential experiments: a versioned representation map, a causal role classifier, a claim-status filter, and an estimand lock. The lock fixes a standardized proximal effect before generated covariates enter the analysis. Under audit correctness and standard identification assumptions, admissible role assignments preserve this estimand. We apply the established conditional-covariance characterization of compression bias to substitution of generated representations for design-relevant states. A standardized decomposition separates compression, conditional-law, and standardization drift. Further results cover mediator adjustment, post-action leakage, marker-intervention conflation, outcome-guided discovery, and state-measurement error. Cluster-level orthogonal estimators distinguish empirical and superpopulation targets under repeated sessions and missing outcomes. Simulations show that refinement helps when it retains design-relevant information, whereas design erasure, leakage, and same-data marker selection can produce bias or undercoverage. The framework places causal semantics and claim status before confirmatory inference with generated representations.

Abstract: Large language models (LLMs) have a growing range of applications in medicine, and their evaluation is critical for ensuring they provide benefit and not harm. This evaluation can be more challenging than traditional machine learning for many reasons, including probabilistic and open-ended outputs, and behavior that shifts with prompt design and accumulated context. This review covers four key areas of LLM evaluation: principles of study design, statistical methods, capability evaluation and clinical context evaluation. Capability evaluation considers different benchmarks, including multiple-choice, agentic and multi-turn benchmarks, alongside operational metrics like token usage. Clinical context evaluation addresses establishing accuracy of free text outputs, such as human review and LLM-as-a-judge, and clinical trial approaches. Across sections, we describe underlying concepts and potential pitfalls, while emphasizing the importance of aligning evaluation methods with the research question. Together, this article aims to provide a pragmatic basis for designing and executing rigorous evaluations of healthcare LLMs.

Abstract: Large language models are superseded every few quarters; clinical evidence takes years. We asked whether medical research is keeping pace with the systems it evaluates. PubMed returned 11,628 records for January 2023 to June 2026 across fourteen clinical domains, growing 45-fold; 2.5% used a randomised, controlled or prospective design. Evaluation lag, from a study's newest named model release to its own publication, widened from 1.33 to 6.08 quarters. Because discontinued models age mechanically, we benchmarked this against a counterfactual holding model composition fixed: migration to newer systems offset only 56% of the drift (95% CI 50-65). Randomised trials evaluated models a median 4.6 quarters older than other designs (P = 3 x 10^-19), yet among studies naming a model still under development no design differed from any other; 62% of randomised trials evaluated a discontinued family. Rigour and currency are in tension, and that tension reflects model selection rather than research timelines.