{"entity": "researcher", "timestamp": "2026-07-20T00:59:29.742Z", "family": "Synofzik", "given": "Matthis", "initials": "M", "orcid": "0000-0002-2280-7273", "affiliations": ["Department of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), University of T\u00fcbingen, T\u00fcbingen, Germany.", "German Center for Neurodegenerative Diseases (DZNE), T\u00fcbingen, Germany."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/7005e3844fd34960a2045bb7febeec57.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/7005e3844fd34960a2045bb7febeec57"}}, "publications": [{"entity": "publication", "iuid": "a3e0296764c54e03ba99681fee25bca5", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a3e0296764c54e03ba99681fee25bca5.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a3e0296764c54e03ba99681fee25bca5"}}, "title": "Longitudinal Analysis of Natural History Progression of Rare and Ultra-Rare Cerebellar Ataxias Using Item Response Theory.", "authors": [{"family": "Hamdan", "given": "Alzahra", "initials": "A", "orcid": "0009-0002-3102-2707", "researcher": {"href": "https://publications.scilifelab.se/researcher/b723248aafce4dcd9bce04164bf6e4ec.json"}}, {"family": "Hendrickx", "given": "Niels", "initials": "N", "orcid": "0009-0000-0951-7514", "researcher": {"href": "https://publications.scilifelab.se/researcher/efbad26df28d450da47e241f85d67dd3.json"}}, {"family": "Hooker", "given": "Andrew C", "initials": "AC", "orcid": "0000-0002-2676-5912", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f2a10ae6b38449aa4865cd073be7f24.json"}}, {"family": "Chen", "given": "Xiaomei", "initials": "X", "orcid": "0009-0002-0663-0532", "researcher": {"href": "https://publications.scilifelab.se/researcher/9dfd2d7e0be5469cb564bc373f24311e.json"}}, {"family": "Comets", "given": "Emmanuelle", "initials": "E", "orcid": "0000-0002-9150-9886", "researcher": {"href": "https://publications.scilifelab.se/researcher/bc3f70e414c248c7b04948c3a4e571d8.json"}}, {"family": "Trasch\u00fctz", "given": "Andreas", "initials": "A", "orcid": "0000-0002-8165-5898", "researcher": {"href": "https://publications.scilifelab.se/researcher/20329d73c37449b1b98a20585e096f32.json"}}, {"family": "Sch\u00fcle", "given": "Rebecca", "initials": "R", "orcid": "0000-0002-7781-2766", "researcher": {"href": "https://publications.scilifelab.se/researcher/24310ee59f694c24beb5cabbfb33b0ea.json"}}, {"family": "ARCA Study Group", "given": "", "initials": ""}, {"family": "EVIDENCE\u2010RND Consortium", "given": "", "initials": ""}, {"family": "Mentr\u00e9", "given": "France", "initials": "F", "orcid": "0000-0002-7045-1275", "researcher": {"href": "https://publications.scilifelab.se/researcher/b72e8bb8370c4cc3ab44f0cc01591370.json"}}, {"family": "Synofzik", "given": "Matthis", "initials": "M", "orcid": "0000-0002-2280-7273", "researcher": {"href": "https://publications.scilifelab.se/researcher/7005e3844fd34960a2045bb7febeec57.json"}}, {"family": "Karlsson", "given": "Mats O", "initials": "MO", "orcid": "0000-0003-1258-8297", "researcher": {"href": "https://publications.scilifelab.se/researcher/8b7ca3868f0b431799ea51c4641d1e5a.json"}}], "type": "journal article", "published": "2024-12-00", "journal": {"title": "Clin. Pharmacol. Ther.", "issn": "1532-6535", "volume": "116", "issue": "6", "pages": "1593-1605", "issn-l": "0009-9236"}, "abstract": "Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra-rare genetic diseases. While disease-modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real-world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75-90% less with 5 years vs. 2 years), and larger drug effects (~ 70-80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well-controlled type I error, compared to total score models or end-of-treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra-rare genetic ataxias.", "doi": "10.1002/cpt.3466", "pmid": "39403821", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [], "notes": [], "created": "2024-11-25T10:09:52.118Z", "modified": "2025-02-28T14:09:44.213Z"}, {"entity": "publication", "iuid": "b2d627809f54443d921bec29619bcc70", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b2d627809f54443d921bec29619bcc70.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b2d627809f54443d921bec29619bcc70"}}, "title": "Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.", "authors": [{"family": "Matalonga", "given": "Leslie", "initials": "L"}, {"family": "Hern\u00e1ndez-Ferrer", "given": "Carles", "initials": "C", "orcid": "0000-0002-8029-7160", "researcher": {"href": "https://publications.scilifelab.se/researcher/9716a4b2dec6496f93e5ea21b1fde8ed.json"}}, {"family": "Piscia", "given": "Davide", "initials": "D"}, {"family": "Solve-RD SNV-indel working group", "given": "", "initials": ""}, {"family": "Sch\u00fcle", "given": "Rebecca", "initials": "R"}, {"family": "Synofzik", "given": "Matthis", "initials": "M", "orcid": "0000-0002-2280-7273", "researcher": {"href": "https://publications.scilifelab.se/researcher/7005e3844fd34960a2045bb7febeec57.json"}}, {"family": "T\u00f6pf", "given": "Ana", "initials": "A"}, {"family": "Vissers", "given": "Lisenka E L M", "initials": "LELM", "orcid": "0000-0001-6470-5497", "researcher": {"href": "https://publications.scilifelab.se/researcher/495b4d9a7db144a08ed311aced872c2a.json"}}, {"family": "de Voer", "given": "Richarda", "initials": "R", "orcid": "0000-0002-8222-0343", "researcher": {"href": "https://publications.scilifelab.se/researcher/baef9b412cbf4b1783f6a1c64913fb30.json"}}, {"family": "Solve-RD DITF-GENTURIS", "given": "", "initials": ""}, {"family": "Solve-RD DITF-ITHACA", "given": "", "initials": ""}, {"family": "Solve-RD DITF-euroNMD", "given": "", "initials": ""}, {"family": "Solve-RD DITF-RND", "given": "", "initials": ""}, {"family": "Tonda", "given": "Raul", "initials": "R"}, {"family": "Laurie", "given": "Steven", "initials": "S"}, {"family": "Fernandez-Callejo", "given": "Marcos", "initials": "M"}, {"family": "Pic\u00f3", "given": "Daniel", "initials": "D"}, {"family": "Garcia-Linares", "given": "Carles", "initials": "C"}, {"family": "Papakonstantinou", "given": "Anastasios", "initials": "A"}, {"family": "Corv\u00f3", "given": "Alberto", "initials": "A"}, {"family": "Joshi", "given": "Ricky", "initials": "R", "orcid": "0000-0003-4463-0453", "researcher": {"href": "https://publications.scilifelab.se/researcher/00d346b9d3a04ddbaaccd612895f7136.json"}}, {"family": "Diez", "given": "Hector", "initials": "H"}, {"family": "Gut", "given": "Ivo", "initials": "I", "orcid": "0000-0001-7219-632X", "researcher": {"href": "https://publications.scilifelab.se/researcher/c14600c4e0d54a7aae393c728d9af088.json"}}, {"family": "Hoischen", "given": "Alexander", "initials": "A"}, {"family": "Graessner", "given": "Holm", "initials": "H", "orcid": "0000-0001-9803-7183", "researcher": {"href": "https://publications.scilifelab.se/researcher/eb6f274e7f494b8f879a92f2ebc0bf30.json"}}, {"family": "Beltran", "given": "Sergi", "initials": "S", "orcid": "0000-0002-2810-3445", "researcher": {"href": "https://publications.scilifelab.se/researcher/86f06a2de0b14260b5bc42c382a83c88.json"}}, {"family": "Solve-RD Consortia", "given": "", "initials": ""}], "type": "journal article", "published": "2021-09-00", "journal": {"title": "Eur. J. Hum. Genet.", "issn": "1476-5438", "volume": "29", "issue": "9", "pages": "1337-1347", "issn-l": "1018-4813"}, "abstract": "Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.", "doi": "10.1038/s41431-021-00852-7", "pmid": "34075210", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41431-021-00852-7"}, {"db": "pmc", "key": "PMC8440686"}], "notes": [], "created": "2021-11-20T12:21:00.311Z", "modified": "2021-11-20T12:21:00.575Z"}]}