ANCHOR Validation Trial in High-Risk Multidisciplinary Care

DESIGN. Pragmatic, multicenter, encounter-level, three-arm parallel randomized controlled trial. 1:1:1 patient-level stratified permuted-block randomization, block size 6, stratified by site and acuity stratum. Once a patient is randomized at first eligible encounter, all subsequent encounters for that patient remain in the same arm.

ARMS.

• Arm 1 (Unassisted standard care, n=80): No LLM. No ANCHOR. The supervising physician opens a blank SOAP note template and writes their own assessment and plan from scratch.
• Arm 2 (Gemini 3.1 Pro with safety prompt, n=80): Gemini 3.1 Pro generates the recommendation under a clinical-safety system prompt, content filters, and retrieval-augmented generation. The supervising physician reviews the LLM output directly. This stack is operationally equivalent to LLM-assisted clinical-decision-support deployments already in routine use at major U.S. health systems.
• Arm 3 (Gemini 3.1 Pro + ANCHOR, n=80): Gemini 3.1 Pro generates the recommendation under the same safety prompt as Arm 2; ANCHOR augments that output with the Logical Neural Network certificate, specialist-agent verification, and concept-decomposed audit trail.

OPERATIONAL SIZING. The Waymark integrated-network workflow across Ohio, Washington, and Virginia captures approximately 20 eligible high-risk multidisciplinary encounters per week. With 12 weeks of active enrolment, total enrolment is 240 encounters (80 per arm at 1:1:1).

POWER CALCULATION. Anchored on the architectural-argument retrospective cohort. For each pairwise contrast at n=80 per arm, the plausible effect range is 5 to 11 percentage points absolute reduction (midpoint 8 percentage points). At the midpoint planning effect (Arm 2 event rate 25 percent versus Arm 3 17 percent), power is approximately 0.50 for the verification-layer-specific contrast (Arm 3 versus Arm 2) at alpha = 0.05. The trial functions as a calibration cohort with effect estimates and 95 percent confidence intervals.

PRIMARY ENDPOINT. Per-encounter binary composite, adjudicated by 3 board-certified physicians blinded to allocation; final scoring by majority of three. Components: (a) Failure to mention a do-not-miss diagnosis; (b) Under-triage; (c) Recommendation of a medication contraindicated by documented allergies/conditions/comorbidities; (d) Failure to recommend escalation when clinically warranted.

PRIMARY CONTRAST: Arm 3 versus Arm 2 (ANCHOR-specific). PRE-SPECIFIED SECONDARY CONTRAST: Arm 2 versus Arm 1 (AI-introduction).

SECONDARY ENDPOINTS (hierarchical fixed sequence, Holm-Bonferroni step-down at family-wise alpha = 0.05): (1) Appropriate triage escalation rate; (2) Time-to-physician-decision; (3) Clinician acceptance rate of ANCHOR flags (Arm 3 only); (4) 30-day emergency-department visit rate (EXPLORATORY); (5) 30-day hospitalization rate (EXPLORATORY); (6) Social-determinants-of-health response composite.

STATISTICAL ANALYSIS. Mixed-effects logistic regression with arm (3-level categorical) as primary fixed-effect predictor and random intercept for patient nested within supervising physician; fixed-effect adjustment for site and acuity stratum. Gatekeeping for the two pairwise contrasts. Pre-specified sensitivity analyses: cluster-robust standard errors at patient level; generalized estimating equations with patient cluster and exchangeable correlation; patient-level aggregated analysis; Bayesian logistic regression with informative prior on the ANCHOR-specific contrast from the retrospective evaluation; exact methods. Missing data via multiple imputation by chained equations (m=20). Intention-to-treat primary with treatment-policy estimand (per ICH E9(R1)); per-protocol sensitivity excluding API-failure encounters. No interim efficacy stop. Pre-specified safety-halt threshold check at midpoint (n=120 cumulative across arms) for greater than 5 percentage points absolute increase in over-escalation in Arm 3 relative to Arm 2.

ANCHOR DIAGNOSTIC-TEST CHARACTERIZATION (independent of trial primary endpoint). ANCHOR's certificate (operational state: hazard flagged / no hazard flagged / out of scope) is characterized as a diagnostic test against adjudicated ground truth: sensitivity, specificity, positive predictive value, negative predictive value, area under the receiver-operating-characteristic curve, and calibration metrics (Expected Calibration Error, Brier score, reliability diagram).

PRE-SPECIFIED ALGORITHMIC FAIRNESS AUDIT. Equalized odds gap, equal opportunity gap, predictive parity gap, and within-subgroup calibration (Brier-difference tolerance 0.05) across race/ethnicity, sex assigned at birth, age band, urban/rural per RUCA 2024, and primary language. Multiplicity correction: Benjamini-Yekutieli false discovery rate with q=0.05. Disparity decision rule (locked pre-unblinding): any pairwise equalized-odds gap exceeding 0.10 with the lower bootstrap 95 percent confidence interval bound greater than 0.05 triggers a Limitations section, mitigation proposal, and a hold on broader deployment until mitigation is validated.

DATA CAPTURE. The 30-day endpoints use Waymark's integrated electronic-health-record + real-time admission/discharge/transfer feed + claims pipeline. ADT events are detected in near-real time across the full network of acute and ambulatory facilities; claims are reconciled at day 30 to confirm capture completeness. Pre-trial registration locked at the Open Science Framework prior to first enrolment; reported under CONSORT-AI 2020.