Validation of the RADIAL Algorithm for Diagnosis of Autosomal Recessive Cerebellar Ataxia (RADIAL-VALID)

RADIAL is an algorithm which has been developed following a review of the literature on 67 autosomal recessive cerebellar ataxias (ARCA) and personal clinical experience. Frequency and specificity of each feature were defined for each autosomal recessive cerebellar ataxia, and corresponding prediction scores were assigned. Clinical and paraclinical features of patients are entered into the algorithm, and a patient's total score for each ARCA is calculated, producing a ranking of possible diagnoses. Sensitivity and specificity of the algorithm were assessed by blinded analysis of a multinational cohort of 834 patients with molecularly confirmed autosomal recessive cerebellar ataxia. The performance of the algorithm was assessed versus a blinded panel of autosomal recessive cerebellar ataxia experts. The correct diagnosis was ranked within the top 3 highest-scoring diagnoses at a sensitivity and specificity of >90% for 84% and 91% of the evaluated genes, respectively. Mean sensitivity and specificity of the top 3 highest-scoring diagnoses were 92% and 95%, respectively. Our aim is now to validate in a prospective cohort of ARCA, the performance of RADIAL to predict the correct genetic diagnosis.

Study Overview

• Status: Recruiting
• Conditions: Autosomal Recessive Cerebellar Ataxia
• Intervention / Treatment: Genetic: Genetic diagnosis (PMDA panel); Diagnostic test: Use of RADIAL algorithm

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tranchant Christine, MD; Phone Number: +33 3 88 12 85 31; Email: christine.tranchant@chru-strasbourg.fr

Study Locations

• France
  • Besançon, France
    • Recruiting
    • CHU de Besancon- Neurology
    • Principal Investigator: Bereau Matthieu, MD
    • Contact: Bereau Matthieu, MD; Phone Number: +33381668166; Email: mbereau@chu-besancon.fr
  • Dijon, France
    • Recruiting
    • CHU de Dijon- Neurology
    • Contact: Moreau Thibault, MD; Phone Number: +33380471248; Email: Thibault.moreau@chu-dijon.fr
    • Principal Investigator: Quentin Thomas, MD
    • Sub-Investigator: Christel Thauvin, MD PhD
    • Sub-Investigator: Laurence Faivre, MD PhD
    • Sub-Investigator: Gwendoline Dupont, MD
    • Sub-Investigator: Vincent Schneider, MD
  • Lille, France
    • Not yet recruiting
    • CHU Lille- Neurology
    • Contact: Devos David, MD; Email: David.DEVOS@CHRU-LILLE.FR
    • Principal Investigator: David Devos, MD
    • Sub-Investigator: Eugénie MUTEZ, MD
  • Marseille, France
    • Recruiting
    • CHU Marseille- Neurology
    • Contact: Azulay Jean-Philippe, MD; Phone Number: +33 491380000; Email: jean-philippe.azulay@ap-hm.fr
    • Principal Investigator: Azulay Jean-Philippe, MD
  • Montpellier, France
    • Recruiting
    • CHU Montpellier - Neurology
    • Contact: Marelli Cecilia, MD; Phone Number: +33 467336733; Email: cecilia.marelli@upmc.fr
    • Principal Investigator: Marelli Cecilia, MD
    • Sub-Investigator: Roubertie Agathe, MD
  • Nancy, France
    • Recruiting
    • CHU Nancy- Neurology
    • Contact: Renaud Mathilde, MD; Phone Number: +33383154500; Email: m.renaud@chru-nancy.fr
    • Principal Investigator: Renaud Mathilde, MD
    • Sub-Investigator: Fismand Solène, MD
  • Strasbourg, France
    • Recruiting
    • CHRU de Strasbourg - Neurology/Pediatrics
    • Contact: Tranchant Christine, MD; Phone Number: +33388128531; Email: christine.tranchant@chru-strasbourg.fr
    • Contact: Anheim Mathieu, MD; Phone Number: +33388128535; Email: mathieu.anheim@chru-strasbourg.fr
    • Sub-Investigator: Laugel Vincent, MD PhD
    • Sub-Investigator: Spitz Marie Aude, MD
    • Sub-Investigator: De Saint Martin Anne, MD
    • Sub-Investigator: Abi Warde Marie Thérèse, MD
    • Sub-Investigator: Iosif Andra Valentina, MD
    • Sub-Investigator: Wirth Thomas, MD
    • Principal Investigator: Tranchant Christine, MD PhD
    • Sub-Investigator: Anheim Mathieu, MD PhD
  • Toulouse, France
    • Recruiting
    • CHU Toulouse- Neurology
    • Principal Investigator: Ory-Magne Fabienne, MD
    • Contact: Ory-Magne Fabienne, MD; Phone Number: +33 561772233; Email: ory.f@chu-toulouse.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

- For patients:

1. Patient, male or female, over 5 years old (no upper age limit)
2. Patient with cerebellar ataxia who started before the age of 40
3. Patient with a family history compatible with autosomal recessive inheritance (sporadic case, consanguinity, several cases in siblings)
4. Patient in which an acquired cause of cerebellar ataxia has been excluded
5. Patient whose genetic diagnosis is unknown (NB: patients with a known negative result for the Friedreich's disease gene are eligible for inclusion))

6. For patients over 18 years old: patient speaking and reading French, able to give a signed and dated informed consent to participate in the study.

   Patients who have reached the age of majority and whose DNA has been banked and who have signed a consent form authorizing the subsequent use of this DNA for research purposes, including genetic analysis of cerebellar ataxias or associated pathologies, and for whom the RADIAL information sheet can be completed in full, are eligible for inclusion.

7. For patient under 18 years old: Tutor or person with parental authority must speak French and be able to give a signed and dated informed consent for the minor patient.

   Patients who are minors, whose DNA has been banked and for whom the parental authority has signed a consent form authorizing the subsequent use of this DNA for research purposes, including genetic analysis of cerebellar ataxias or associated pathologies, and for whom the RADIAL information sheet can be completed, are eligible.

8. Patient affiliated to the French national health insurance

   - For relatives:

9. Male or female, over 18 years old (no upper age limit)
10. Biological father or mother of a patient included in RADIAL-VALID research protocol
11. (for prospective inclusion only) To be available for a visit to the participating center where the child is being followed
12. Speaking and reading French, able to give a signed and dated informed consent to participate in the study

13. Subject affiliated to the French national health insurance

    Exclusion Criteria:

    - For patients:

14. Patient in whom targeted sequencing of a panel of PMDA genes and/or exome/genome sequencing have already been performed.

    • For patients and related:
15. Subject of a legal protection measure
16. Subject in exclusion period (determined by previous or current study)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: experimental arm; The analysis of phenotypic data in RADIAL and the analysis of DNA (analysis of the Friedreich gene ± PMDA panel) will be performed for all patients in order to meet the main objective and the secondary objectives. Specifically for the secondary objectives (N ° 3, 4 and 5), randomization via eCRF (electronic case report form) will be performed for the interpretation of genetic analyzes (PMDA panel) without inducing any change for the patients. This randomization, by block and by center, will allow the attribution of one of the following two groups: Control group: interpretation of genetic analyzes without the use of RADIAL;; Experimental group: interpretation of genetic analyzes using RADIAL. Genome analysis (secondary objective n ° 6) will be carried out for all the patients who remained without diagnosis at the end of the first part, and for whom the DNA of relatives is available.

Genetic: Genetic diagnosis (PMDA panel); Blood samples for DNA study; Diagnostic test: Use of RADIAL algorithm; RADIAL card filling (contains clinical and biological data)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients for whom the final genetic diagnosis is in the top 3 of the diagnoses proposed by the RADIAL algorithm (corresponding to the diseases with the 3 highest score given by the algorithm).	The final diagnosis will be established after a genetic analysis and a medical interpretation of the results by geneticists.	At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients for whom the final genetic diagnosis is the first diagnosis proposed by the RADIAL algorithm (corresponding to the disease with the highest score given by the algorithm).		At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit)
Comparison of interpretation times by the clinical-genetic team (genetic and clinical data) with and without the help of the RADIAL algorithm	Randomization is a methodological refinement that is only useful for this secondary endpoint (does not relate to the primary endpoint). The clinical and paraclinical data of all patients will be treated in the same way, and randomization concerns only the use of RADIAL made by the data biologist in sample processing. There is therefore no randomization of subjects but only of genetic results. At the genetic study stage (Panel PMDA panel), for the patient group randomized "with RADIAL results", the interpretation of genetic data (and in particular of the different variants found) will be done aware of the results given by RADIAL, and in the randomized group "without results RADIAL ", the analysis of the genetic data will be done in the absence of knowledge of the results provided by RADIAL.	At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit)
Comparison of the satisfaction score given by the clinical-genetic team in the interpretation of data with and without the help of the RADIAL algorithm	Randomization is a methodological refinement that is only useful for this secondary endpoint (does not relate to the primary endpoint). The clinical and paraclinical data of all patients will be treated in the same way, and randomization concerns only the use of RADIAL made by the data biologist in sample processing. There is therefore no randomization of subjects but only of genetic results. At the genetic study stage (Panel PMDA panel), for the patient group randomized "with RADIAL results", the interpretation of genetic data (and in particular of the different variants found) will be done aware of the results given by RADIAL, and in the randomized group "without results RADIAL ", the analysis of the genetic data will be done in the absence of knowledge of the results provided by RADIAL.	At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit)
Influence of RADIAL on genetic diagnosis: percentage of patients whose diagnosis has been reviewed after the clinical-genetic team has learned of the results proposed by RADIAL	Randomization is a methodological refinement that is only useful for this secondary endpoint (does not relate to the primary endpoint). The clinical and paraclinical data of all patients will be treated in the same way, and randomization concerns only the use of RADIAL made by the data biologist in sample processing. There is therefore no randomization of subjects but only of genetic results. At the genetic study stage (Panel PMDA panel), for the patient group randomized "with RADIAL results", the interpretation of genetic data (and in particular of the different variants found) will be done aware of the results given by RADIAL, and in the randomized group "without results RADIAL ", the analysis of the genetic data will be done in the absence of knowledge of the results provided by RADIAL.	At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit)
Percentage of patients for whom the genome analysis will have detected a new gene.	If no diagnosis is established after the PMDA + RADIAL analyzes, additional genetic analyzes will be carried out for patient and for relatives (genome). These new analyzes should help to define the diagnosis of the patient.	At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit)

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France
• Investigators: Principal Investigator: Tranchant Christine, MD, CHRU Strasbourg

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2021
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: February 5, 2020
• First Submitted That Met QC Criteria: February 5, 2020
• First Posted (Actual): February 7, 2020

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 20, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: algorithm; autosomal recessive cerebellar ataxia; genetic diagnosis
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Cerebellar Diseases; Ataxia; Cerebellar Ataxia
• Other Study ID Numbers: 7346

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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