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Validation of a Clinical Algorithm for the Diagnosis of Recessive Ataxias (BASE-AAR)

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ClinicalTrials.gov Identifier: NCT04099914
Recruitment Status : Recruiting
First Posted : September 23, 2019
Last Update Posted : March 10, 2020
Sponsor:
Collaborators:
Neurology Department, CHU de Strasbourg-France
Genetic Department , CHU Montpellier-France
Information provided by (Responsible Party):
University Hospital, Montpellier

Brief Summary:

The field of clinical diagnosis of recessive cerebellar ataxias (ARCA) is particularly complex and Next Generation Sequencing (NGS) techniques have revolutionized this neuro-genetic field. The current challenge is to optimize the analysis of genetic data generated by NGS because: the processing of data remains very laborious; diagnostic yeld less than 50%; the interpretation of the variants sometimes very difficult. For this purpose of optimization, the team of the University Hospital of Strasbourg has developed a computer algorithm based on 124 clinical and para-clinical parameters (derived from the data of the literature), useful to guide the genes to be targeted in priority by genetic analysis, in the context of a suspicion of ARCA (> 60 known genes); this algorithm was validated retrospectively in 834 patients with genetically confirmed ARCA (92% Sense, 95% Spec). However, these 834 patients are often the same as those described in the literature and used for the elaboration of the algorithm. This introduces a bias in the initial evaluation of the algorithm, which therefore requires validation in clinical practice, from a cohort of patients referred for suspected ARCA (with or without a found genetic mutation). At the same time, Montpellier's genetics laboratory has developed a bioinformatic method for the search for copy number variations (CNV) that can be applied in a targeted manner to the genes predicted by the algorithm.

The principal aim of this study is the validation of a semi-automated clinical algorithm for NGS molecular diagnosis of ARCA; the secondary objective is to evaluate if the application of this algorithm coupled with a targeted bioinformatic analysis can increase the diagnostic yield of the NGS analysis.


Condition or disease
Ataxia

Detailed Description:
Design: Retrospective study based on clinico-genetic data. Total research duration: 22 months Plan of the study : More than 150 patients referred for ARCA suspicion have been analyzed by NGS (Montpellier platform) since September 2013. The clinical data of these patients will be entered at the computer level into the algorithm to obtain the prediction of the gene involved (under the form of a probability for each of the genes known to ARCA). The investigators will compare this result with that obtained by standard NGS analysis. For patients without molecular diagnosis defined after standard NGS analysis, the investigators will take the 5 most probable genes selected on the basis of the algorithm in order to carry out an in-depth analysis of the variants found and a bioinformatic analysis by semi-automatic detection of CNVs. Main Evaluation Criterion: Concordance of the algorithm with standard NGS analysis for the genetic diagnosis of ARCA. Secondary evaluation criterion:% of patients for whom the prediction based on the algorithm suggested the correct diagnosis (subsequently confirmed after revision in the detail of the genetic data) while the standard genetic analysis was not not informative. Statistical Analysis: The investigators will perform a concordance analysis (Cohen's k) to validate the algorithm in clinical practice. For a given patient, there will be concordance if: i) one of the first 5 genes predicted with the highest probability by the algorithm is compatible with the mutation found after standard NGS or ii) if no gene is predicted by the algorithm (score <20) and no mutation found by NGS analysis.

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Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Case-Only
Time Perspective: Retrospective
Official Title: Exploitation of a BAse of Genetic Data (Obtained by Next Generation SEquencing) for the Validation of a Clinical Algorithm for the Diagnosis of Recessive Cerebellar Ataxias
Actual Study Start Date : November 1, 2019
Estimated Primary Completion Date : December 15, 2021
Estimated Study Completion Date : December 31, 2021





Primary Outcome Measures :
  1. Agreement between the prediction of the algorithm and the result of the standard NGS analysis [ Time Frame: 1 day ]
    In order to validate in clinical practice a semi-automated clinical algorithm designed to guide the molecular diagnosis obtained by Next Generation Sequencing (NGS) in patients with suspected Autosomal Recessive Cerebellar Ataxia (ARCA), we will measure the agreement between the prediction of the algorithm and the result of the standard NGS analysis. For each patient the agreement is defined as: 1) one of the first 5 gene predicted with the highest probability by the algorithm is also the mutated gene found after the NGS analysis; 2) if no gene is predicted by the algorithm (= none of the gene has a prediction score > 20) and no mutation is found after NGS analyses.


Secondary Outcome Measures :
  1. Percentage of patients for whom the prediction based on the algorithm suggested the right diagnosis, while the standard NGS analysis was not informative [ Time Frame: 1 day ]
    The secondary objective is to evaluate whether the application of this algorithm, coupled with a targeted bioinformatic analysis, changes the diagnostic yield compared to a NGS analysis performed in a conventional manner. Therefore, the secondary outcome will be the percentage of patients for whom the prediction based on the algorithm suggested the corrected diagnosis (confirmed in a second time after the review of the genetic data derived from NGS after the application of a targeted bioinformatic analysis), while the standard NGS analysis (blinded to algorithm prediction) was not informative


Biospecimen Retention:   Samples With DNA
Genetic database of approximately 150 patients with cerebellar ataxia, referred since September 2013 for exome analysis to the Montpellier University Hospital Center. The genetic data are from clinical exome capture sequencing with the Trusight One sequencing panel kit (www.illumina.com/trusightone), allowing exploration of approximately 5,000 human disease genes. Each sample is accompanied by a consent that allows genetic analysis and data processing. Each sample is also accompanied by clinical information, usually consisting of a clinical information sheet adapted to patients with genetic ataxias or clinical reports. These data are already accessible.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Adut Patients with suspicion of recessive cerebellar ataxia , with onset before the age of 50 and with negative molecular analisys for Friedreich ataxia and dominant spinocerebellar ataxias due to trinucleotide expansion. .
Criteria

Inclusion criteria:

- having a predominant phenotype of pure or complex cerebellar ataxia of probable genetic origin (after exclusion of acquired, inflammatory, tumoral, infectious or toxic forms) - having started before the age of 50; - evoking a modality of recessive transmission (sporadic cases, brothers or sister affected, consanguinity of the parents) - in which dominant genetic forms due to CAG expansion (SCA1, SCA2, SCA3, SCA6, SCA7) and pre-mutation of the FMR1 gene (if onset after age 45)

Exclusion criteria:

- objecting to the computer processing of the data contained in the medical file.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04099914


Contacts
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Contact: Cecilia Marelli, MD 633376029 ext 33 c-marelli@chu-montpellier.fr

Locations
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France
Uh Montpellier Recruiting
Montpellier, France, 34295
Contact: Cecilia Marelli, MD    633376029 ext 33    c-marelli@chu-montpellier.fr   
Sponsors and Collaborators
University Hospital, Montpellier
Neurology Department, CHU de Strasbourg-France
Genetic Department , CHU Montpellier-France
Investigators
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Principal Investigator: Cecilia Marelli, MD University Hospitals of Montpellier
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Responsible Party: University Hospital, Montpellier
ClinicalTrials.gov Identifier: NCT04099914    
Other Study ID Numbers: RECHMPL18_0431
First Posted: September 23, 2019    Key Record Dates
Last Update Posted: March 10, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: NC

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Montpellier:
Cerebellar ataxia
Neurogenetics
Next generation sequence
Clinical algorithm
Additional relevant MeSH terms:
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Ataxia
Cerebellar Ataxia
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases