AI-assisted Rare Disease Diagnosis

A Multicentre Randomised Controlled Trial of LLM-Assisted Diagnostic Support in Patients With Suspected Rare or Diagnostically Unresolved Disease

A multicentre randomised controlled trial evaluating whether a rare-disease diagnostic large language model can improve diagnostic quality, efficiency, and health-economic outcomes for physicians managing patients with suspected rare or diagnostically unresolved disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Rare Diseases; Rare Disorders
• Intervention / Treatment: Other: AI system

Detailed Description

Rare disease patients commonly experience prolonged diagnostic odysseys rooted in limited rare disease recognition, phenotypic heterogeneity, and dispersed diagnostic clues. Diagnostic decision-support large language models may improve first-visit consultations by integrating prior records, generating structured analyses, and proposing candidate diagnoses, thereby shortening diagnostic pathways and improving appropriate genetic testing referral.

Participating physicians will provide care under both AI-assisted and standard diagnostic workflows. Eligible patients will be individually randomised to receive either AI-assisted diagnostic support or standard clinical practice.

In the intervention arm, physicians will have diagnostic support from AI when seeing patients. In the control arm, patients are seen under standard hospital workflow without any generative AI tools. Outcomes adjudicated by an independent Expert Committee blinded to arm assignment; adjudicators access no AI-generated materials.

A prospective within-trial economic evaluation will be conducted alongside the randomized trial. Healthcare resource use and costs associated with the diagnostic pathway will be collected.

• Study Type: Interventional
• Enrollment (Estimated): 1056
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Shuyang Zhang, MD, PhD; Phone Number: +86-13911667211; Email: shuyangzhang103@163.com

Study Locations

• China
  • Beijing, China
    • Peking Union Medical College Hospital
    • Contact: Shuyang Zhang; Phone Number: +86-13911667211; Email: shuyangzhang103@163.com
  • Cangzhou, China
    • Cangzhou Central Hospital
    • Contact: Yong Li; Phone Number: +86-0317-2075013; Email: czszxyyirb@163.com
  • Changchun, China
    • Changchun Sacred Heart Hospital
  • Dongguan, China
    • Dongguan People's Hospital
  • Foshan, China
    • First People's Hospital of Foshan
  • Guiyang, China
    • Guizhou Provincial People's Hospital
  • Jilin City, China
    • Jilin Central General Hospital
  • Kunming, China
    • The First People's Hospital of Yunnan Province
  • Tianjin, China
    • Tianjin Children's Hospital
  • Tianshui, China
    • Tianshui 407 Hospital
    • Contact: Rong Sun; Phone Number: +86-0938-8229999; Email: ts407yy@sina.com
  • Wuhai, China
    • Wuhai People's Hospital
  • Xining, China
    • Qinghai Provincial People's Hospital
  • Zhangzhou, China
    • Zhangzhou Municipal Hospital of Fujian Province

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Patient Inclusion Criteria:

• Any age. Legal guardian co-signs consent for minors or individuals lacking legal capacity.
• Diagnostically unresolved or suspected rare disease, with at least one prior complete clinical evaluation at a secondary-level or higher institution yielding no confirmed explanatory diagnosis.
• First presentation to the enrolling institution for the current condition, with no prior records in the institutional HIS or outpatient system.
• No prior genetic testing related to the current condition; no results or reports available.
• Written informed consent provided voluntarily by patient or legal guardian, with commitment and ability to complete structured follow-up.

Patient Exclusion Criteria:

• Confirmed diagnosis (clinical, pathological, or molecular) explaining the primary symptoms.
• Emergency presentation, critical illness, or any condition incompatible with trial participation.
• Neither patient nor legally authorised proxy able to complete follow-up.
• Concurrent enrollment in another interventional study with diagnostic accuracy or genetic testing yield as a primary endpoint.
• Prior use of another AI system has already yielded a confirmed diagnosis for the current condition.

Physician Inclusion Criteria

• Licensed physician in internal medicine, neurology, pediatrics, general medicine, rare disease, or a related specialty.
• ≥2 years of clinical practice; competent to manage rare disease patients; stratified into junior or senior tier.
• Voluntary participation with written informed consent.

Physician Exclusion Criteria

• No longer in clinical practice, or unable to fulfill required outpatient duties during the study period.
• Unwilling to provide informed consent or to permit protocol-required collection of consultation and questionnaire data.
• Currently enrolled in another AI-assisted clinical workflow, or expected to be unable to comply with the procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AI system; AI system will be used to provide diagnostic support during the encounter in addition to conventional clinical workflow. Use of other generative AI tools is prohibited.	Other: AI system; The study AI system will be used to provide diagnostic support during the clinical encounter, including structuring relevant clinical information, generating a clinical analysis, and suggesting candidate diagnoses for review by the treating physician.
No Intervention: Standard of care; The physician conducts the encounter per standard hospital workflow using conventional clinical resources only. Use of any generative AI tool is prohibited.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Correct Diagnostic Yield	The proportion of all randomised patients whose clinical diagnosis by the end of follow-up is concordant with the blinded-adjudicated final reference diagnosis determined by an independent committee.	From the first visit to final reference diagnosis adjudication, an average of 8 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physician-Reported Experience	Physicians will assess their experience of the diagnostic workflow. Responses will be recorded using a standardized rating scale (range 1-5, where higher scores indicate more positive experience).	Assessed at each consultation (day 1), within 1 day.
Patient-Reported Experience	Patients will assess their experience of the diagnostic workflow. Responses will be recorded using a standardized rating scale (range 1-5, where higher scores indicate more positive experience).	Assessed at each consultation (day 1), within 1 day.
Appropriate Genetic Testing Recommendation Rate	The proportion of randomized patients for whom physician-recommended genetic testing is concordant with the indication determined by an independent genetics adjudication committee.	From the initial consultation to genetic testing indication adjudication, approximately 8 weeks
Candidate Diagnostic Accuracy	The agreement between physician-provided candidate diagnoses in the the initial consultation and the independently adjudicated reference diagnosis.	From the first visit to final reference diagnosis adjudication, an average of 8 weeks.
Molecular Diagnostic Yield	The proportion of all randomized patients in whom genetic testing performed as part of the clinical diagnostic pathway identifies a clinically relevant molecular finding that is confirmed through independent genetics review.	From the first visit to final reference diagnosis adjudication, an average of 8 weeks.
Time to a Correct Diagnosis	The number of days from the first study visit to the first physician-assigned diagnosis that is subsequently confirmed as concordant with the independently adjudicated reference diagnosis.	From enrollment to the end of follow-up, up to 8 weeks.
Duration of the Initial Physician Consultation	In-room consultation time will be recorded, measured, and compared between arms.	Assessed at each consultation (day 1), within 1 day.

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Collaborators: Guizhou Provincial People's Hospital; First People's Hospital of Foshan; Dongguan People's Hospital; Qinghai People's Hospital; Cangzhou Central Hospital; The First People's Hospital of Yunnan; Tianjin Children's Hospital; Zhangzhou Municipal Hospital
• Investigators: Principal Investigator: Shuyang Zhang, MD, PhD, Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: June 7, 2026
• First Submitted That Met QC Criteria: June 14, 2026
• First Posted (Actual): June 16, 2026

Study Record Updates

• Last Update Posted (Actual): July 27, 2026
• Last Update Submitted That Met QC Criteria: July 24, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: diagnosis; cost-effectiveness; AI; rare diseases; LLM
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Disease; Rare Diseases; Artificial Intelligence; Algorithms; Mathematical Concepts; Intelligent Systems
• Other Study ID Numbers: PUMCH I-26PJ0002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No