The Italian National Registry for FSHD: An Enhanced Data Integration and an Analytics Framework Towards Smart Health Care and Precision Medicine for a Rare Disease

Abstract BACKGROUNDThe Italian Clinical network for FSHD (ICNF) has established the Italian National Registry for FSHD (INRF), collecting data from patients affected by Facioscapulohumeral dystrophy (FSHD) and their relatives. The INRF has gathered data from molecular analysis, clinical evaluation, anamnestic information, and family history from more than 3500 participants. METHODSA data management framework, called MOMIS FSHD Web Platform, has been developed to provide charts, maps and search tools customized for specific needs. Patients’ samples and their clinical information derives from the Italian Clinical network for FSHD (ICNF), a consortium consisting of fourteen neuromuscular clinics distributed across Italy. The tools used to collect, integrate, and visualize clinical, molecular and natural history information about patients affected by FSHD and their relatives are described.RESULTSThe INRF has collected the molecular data of FSHD conducted on 7197 subjects, and identified 3362 individuals carrying a DRA: 1634 are unrelated individuals, 602 isolated cases. In 1032 cases the molecular testing has been extended to 3747 relatives, 1728 carrying a DRA. Since 2009 molecular analysis has been accompanied by clinical evaluation based standardized evaluation protocols. In total 3577 clinical forms have been collected, 2059 follow the Comprehensive Clinical Evaluation form (CCEF). The integration of standardized clinical information and molecular data has made possible to demonstrate the wide phenotypic variability of FSHD. The MOMIS (Mediator Environment for Multiple Information Sources) data integration framework allowed performing genotype-phenotype correlation studies, and generated information of medical importance either for clinical practice or genetic counseling.CONCLUSIONThe platform implemented for the FSHD Registry data collection based on OpenClinica meets the requirement to integrate patient/disease information, as well as the need to adapt dynamically to security and privacy concerns. Our results indicate that the quality of data collection in a multi-integrated approach is fundamental for clinical and epidemiological research in a rare disease and allows to redefine diagnostic criteria and disease markers for FSHD.

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Molecular analysis confirms Laurenciella marilzae (Rhodophyta, Rhodomelaceae) in the Mediterranean Sea, a species often misidentified as Laurencia dendroidea

Botanica Marina ◽

10.1515/bot-2020-0030 ◽

2020 ◽

Vol 63 (6) ◽

pp. 527-535

Author(s):

Donatella Serio ◽

Giovanni Furnari ◽

Yola Metti

Keyword(s):

Mediterranean Sea ◽

Molecular Analysis ◽

Molecular Data ◽

Integrative Approach ◽

Molecular Analyses ◽

The Mediterranean ◽

Laurencia Majuscula

AbstractIt was noted that Mediterranean specimens collected at different stations from around Sicily, Italy and referred to as Laurencia dendroidea (as Laurencia majuscula) were similar to the recently described species Laurenciella marilzae. Presented in this study are the results of an integrative approach using both morphology and molecular data (COI-5P + rbcL) to establish which taxon these specimens should be referred to. Molecular analyses show these specimens belong to Laurenciella, and strongly suggest they are within the species L. marilzae. Morphological examinations of these Mediterranean specimens were also detailed and found to support the conclusion that they belong to L. marilzae.

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A Detailed Catalogue of Multi-Omics Methodologies for Identification of Putative Biomarkers and Causal Molecular Networks in Translational Cancer Research

International Journal of Molecular Sciences ◽

10.3390/ijms22062822 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2822

Author(s):

Efstathios Iason Vlachavas ◽

Jonas Bohn ◽

Frank Ückert ◽

Sylvia Nürnberg

Keyword(s):

Cancer Research ◽

Clinical Information ◽

Disease Diagnosis ◽

Molecular Data ◽

Molecular Networks ◽

Biological Knowledge ◽

Omics Data ◽

Translational Cancer Research ◽

Using Data ◽

Biological Entities

Recent advances in sequencing and biotechnological methodologies have led to the generation of large volumes of molecular data of different omics layers, such as genomics, transcriptomics, proteomics and metabolomics. Integration of these data with clinical information provides new opportunities to discover how perturbations in biological processes lead to disease. Using data-driven approaches for the integration and interpretation of multi-omics data could stably identify links between structural and functional information and propose causal molecular networks with potential impact on cancer pathophysiology. This knowledge can then be used to improve disease diagnosis, prognosis, prevention, and therapy. This review will summarize and categorize the most current computational methodologies and tools for integration of distinct molecular layers in the context of translational cancer research and personalized therapy. Additionally, the bioinformatics tools Multi-Omics Factor Analysis (MOFA) and netDX will be tested using omics data from public cancer resources, to assess their overall robustness, provide reproducible workflows for gaining biological knowledge from multi-omics data, and to comprehensively understand the significantly perturbed biological entities in distinct cancer types. We show that the performed supervised and unsupervised analyses result in meaningful and novel findings.

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The Indo-Pacific Amalda (Neogastropoda, Olivoidea, Ancillariidae) revisited with molecular data, with special emphasis on New Caledonia

European Journal of Taxonomy ◽

10.5852/ejt.2020.706 ◽

2020 ◽

Author(s):

Yuri I. Kantor ◽

Magalie Castelin ◽

Alexander Fedosov ◽

Philippe Bouchet

Keyword(s):

Gene Flow ◽

Molecular Analysis ◽

New Caledonia ◽

Narrow Range ◽

Regional Scale ◽

Molecular Data ◽

Shell Morphology ◽

Species Limits ◽

South West ◽

Strait Of Malacca

In the ancillariid genus Amalda, the shell is character rich and 96 described species are currently treated as valid. Based on shell morphology, several subspecies have been recognized within Amalda hilgendorfi, with a combined range extending at depths of 150–750 m from Japan to the South-West Pacific. A molecular analysis of 78 specimens from throughout this range shows both a weak geographical structuring and evidence of gene flow at the regional scale. We conclude that recognition of subspecies (richeri Kilburn & Bouchet, 1988, herlaari van Pel, 1989, and vezzaroi Cossignani, 2015) within A. hilgendorfi is not justified. By contrast, hilgendorfi-like specimens from the Mozambique Channel and New Caledonia are molecularly segregated, and so are here described as new, as Amalda miriky sp. nov. and A. cacao sp. nov., respectively. The New Caledonia Amalda montrouzieri complex is shown to include at least three molecularly separable species, including A. allaryi and A. alabaster sp. nov. Molecular data also confirm the validity of the New Caledonia endemics Amalda aureomarginata, A. fuscolingua, A. bellonarum, and A. coriolis. The existence of narrow range endemics suggests that the species limits of Amalda with broad distributions, extending, e.g., from Japan to Taiwan (A. hinomotoensis) or even Indonesia, the Strait of Malacca, Vietnam and the China Sea (A. mamillata) should be taken with caution.

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Abstract 229: What is the Real Incidence of Out-Of-Hospital Cardiac Arrest in Norway

Circulation ◽

10.1161/circ.140.suppl_2.229 ◽

2019 ◽

Vol 140 (Suppl_2) ◽

Author(s):

Ingvild B Tjelmeland ◽

Morten Larsen ◽

Eirik Skogvoll ◽

Jo Kramer-Johansen

Keyword(s):

Cardiac Arrest ◽

Data Collection ◽

National Registry ◽

Population Incidence ◽

Ambulance Dispatch ◽

High Incidence ◽

Close Relationship ◽

Low Incidence ◽

Study Sites ◽

Hospital Cardiac Arrest

Purpose of the study: The Norwegian Cardiac Arrest Registry (NorCAR) is a mandatory national registry of resuscitation attempts that monitors the population incidence, care and outcome for cardiac arrest. Previously, substantial differences in the number of included patients per 100 000 inhabitants were observed in some “atypical” health trusts (HT). It was not known if this is a problem with data collection or reflected genuine population differences. The purpose of this study was to identify all patients that fill NorCAR’s inclusion criteria among these HTs, by imposing consistent methods for data collection. Materials and methods: The registry implemented consistent, standardised and rigorous data collection methods including targeted audits in four “atypical” health trusts, two with a high and two with a low reported population incidence. Registrations from January to March 2019 was compared with similar results from 2018. Results: In 2018, the observed nationwide annual incidence of out-of-hospital cardiac arrest was 64 per 100 000 inhabitants, varying from 40 to 102. At the four study sites the observed population incidence was stable among HT with high incidence (88 and 110) but apparently increased in the two HTs with previous low incidence after implementation of standardised collection method (from 48 to 56, and 46 to 54). Conclusions: The previously “atypical” low incidence probably reflected a problem with data collection. To achieve full coverage of the population, all data collectors need to collect data using the same method with a concise and thorough investigation of ambulance-, air ambulance-, dispatch-, and hospital records. Data collectors need to have a close relationship with ambulance and dispatch, and constant reminders and feedback on reported results are important. Implementing a new method for data collection takes time, and results need to be evaluated over time.

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Tackling rare diseases: Clinical trials on chips

Experimental Biology and Medicine ◽

10.1177/1535370220924743 ◽

2020 ◽

Vol 245 (13) ◽

pp. 1155-1162 ◽

Cited By ~ 2

Author(s):

Sandra H Blumenrath ◽

Bo Y Lee ◽

Lucie Low ◽

Ranjini Prithviraj ◽

Danilo Tagle

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Data Collection ◽

Rare Disease ◽

Study Design ◽

Rare Diseases ◽

Working Group ◽

Design Data ◽

Chip Technology ◽

Microphysiological Systems

Technological advances with organs-on-chips and induced pluripotent stem cells promise to overcome hurdles associated with developing medical products, especially for rare diseases. Organs-on-chips—bioengineered “microphysiological systems” that mimic human tissue and organ functionality—may overcome clinical trial challenges with real-world patients by offering ways to conduct “clinical trials-on-chips” (CToCs) to inform the design and implementation of rare disease clinical studies in ways not possible with other culture systems. If applied properly, CToCs can substantially impact clinical trial design with regard to anticipated key outcomes, assessment of clinical benefit and risk, safety and tolerability profiles, population stratification, value and efficiency, and scalability. To discuss how tissue chips are best used to move the development of rare disease therapies forward, a working group of experts from industry, academia, and FDA as well as patient representatives addressed questions related to disease setting, test agents for microphysiological systems, study design and feasibility, data collection and use, the benefits and risks associated with this approach, and how to engage stakeholders. While rare diseases with no current therapies were considered the ultimate target, participants cautioned against stepping onto too many unknown territories when using rare disease as initial test beds. Among the disease categories considered ideal for initial CToC tests were well-defined diseases with known clinical outcomes; diseases where tissues on chips can serve as an alternative to risky first-in-human studies, such as in pediatric oncology; and diseases that lend itself to immuno-engineering or genome editing. Participants also considered important challenges, such as hosting the chip technology in-house, the high variability of cell batches and the resulting regulatory concerns, as well as the financial risk associated with the new technology. To make progress in this area and increase confidence with the use of tissue chips, the re-purposing of approved drugs ought to be the very first step. Impact statement Designing and conducting clinical trials are extremely difficult in rare diseases. Adapting tissue chips for rare disease therapy development is pivotal in assuring that treatments are available, especially for severe diseases that are difficult to treat. Thus far, the NCATS-led National Institutes of Health (NIH) Tissue Chip program has focused on deploying the technology towards in vitro tools for safety and efficacy assessments of therapeutics. However, exploring the feasibility and best possible approach to expanding this focus towards the development phase of therapeutics is critical to moving the field of CToCs forward and increasing confidence with the use of tissue chips. The working group of stakeholders and experts convened by NCATS and the Drug Information Association (DIA) addresses important questions related to disease setting, test agents, study design, data collection, benefit/risk, and stakeholder engagement—exploring both current and future best use cases and important prerequisites for progress in this area.

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A molecular phylogeny of Callianassidae and related families (Crustacea : Decapoda : Axiidea) with morphological support

Invertebrate Systematics ◽

10.1071/is19021 ◽

2020 ◽

Vol 34 (2) ◽

pp. 113 ◽

Cited By ~ 3

Author(s):

Rafael Robles ◽

Peter C. Dworschak ◽

Darryl L. Felder ◽

Gary C. B. Poore ◽

Fernando L. Mantelatto

Keyword(s):

Bayesian Analysis ◽

Molecular Analysis ◽

Single Species ◽

Molecular Data ◽

Total Evidence ◽

Morphological Data ◽

12S Rrna ◽

New Genera ◽

Key Species ◽

The Family

The axiidean families Callianassidae and Ctenochelidae, sometimes treated together as Callianassoidea, are shown to represent a monophyletic taxon. It comprises 265 accepted species in 74 genera, twice this number of species if fossil taxa are included. The higher taxonomy of the group has proved difficult and fluid. In a molecular phylogenetic approach, we inferred evolutionary relationships from a maximum-likelihood (ML) and Bayesian analysis of four genes, mitochondrial 16S rRNA and 12S rRNA along with nuclear histone H3 and 18S rRNA. Our sample consisted of 298 specimens representing 123 species plus two species each of Axiidae and Callianideidae serving as outgroups. This number represented about half of all known species, but included 26 species undescribed or not confidently identified, 9% of all known. In a parallel morphological approach, the published descriptions of all species were examined and detailed observations made on about two-thirds of the known fauna in museum collections. A DELTA (Description Language for Taxonomy), database of 135 characters was made for 195 putative species, 18 of which were undescribed. A PAUP analysis found small clades coincident with the terminal clades found in the molecular treatment. Bayesian analysis of a total-evidence dataset combined elements of both molecular and morphological analyses. Clades were interpreted as seven families and 53 genera. Seventeen new genera are required to reflect the molecular and morphological phylograms. Relationships between the families and genera inferred from the two analyses differed between the two strategies in spite of retrospective searches for morphological features supporting intermediate clades. The family Ctenochelidae was recovered in both analyses but the monophyly of Paragourretia was not supported by molecular data. The hitherto well recognised family Eucalliacidae was found to be polyphyletic in the molecular analysis, but the family and its genera were well defined by morphological synapomorphies. The phylogram for Callianassidae suggested the isolation of several species from the genera to which they had traditionally been assigned and necessitated 12 new generic names. The same was true for Callichiridae, with stronger ML than Bayesian support, and five new genera are proposed. Morphological data did not reliably reflect generic relationships inferred from the molecular analysis though they did diagnose terminal taxa treated as genera. We conclude that discrepancies between molecular and morphological analyses are due at least in part to missing sequences for key species, but no less to our inability to recognise unambiguously informative morphological synapomorphies. The ML analysis revealed the presence of at least 10 complexes wherein 2–4 cryptic species masquerade under single species names.

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Multi-instar descriptions of cave dwelling Erythraeidae (Trombidiformes: Parasitengona) employing an integrative approach

Zootaxa ◽

10.11646/zootaxa.4717.1.10 ◽

2019 ◽

Vol 4717 (1) ◽

pp. 137-184 ◽

Cited By ~ 1

Author(s):

SAMUEL GEREMIAS DOS SANTOS COSTA ◽

HANS KLOMPEN ◽

LEOPOLDO FERREIRA DE OLIVEIRA BERNARDI ◽

LUCIANA CARDOSO GONÇALVES ◽

DANTE BATISTA RIBEIRO ◽

...

Keyword(s):

Life Cycle ◽

Cytochrome Oxidase ◽

Molecular Analysis ◽

Species Delimitation ◽

Morphological Changes ◽

Molecular Data ◽

Coi Gene ◽

Integrative Approach ◽

Larval Instars ◽

Individual Host

The life cycle of Parasitengona includes major morphological changes precluding an instar association based only on the morphology. This makes rearing and/or molecular data necessary to associate the heteromorphic instars. Most of the described species are known from either post larval instars or larva. Following a previous study on Palearctic Erythraeidae, in the present study the instar association was made through an integrative approach including rearing trials and molecular analysis of the cytochrome oxidase I (COI) gene with the Bayesian Generalized Mixed Yule Coalescent (bGMYC) algorithm for species delimitation. Two new cave dwelling Erythraeidae (Trombidiformes: Parasitengona) species are described Lasioerythraeus jessicae sp. nov. and Leptus sidorchukae sp. nov. including all active instars. Additionally, a complete description of the previously unknown adults of Charletonia rocciai Treat & Flechtmann, 1979 is provided with notes on the larva and deutonymph. We also demonstrate experimentally that Ch. rocciai larvae are not attached to the same individual host during the entire feeding stage. We discuss the presence of troglomorphisms in Le. sidorchukae sp. nov.; and the distribution of the species.

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Molecular data consistently recover a 'Queensland clade' of Synostemon Phyllanthaceae, Phyllantheae) with distinctive floral morphology

Australian Systematic Botany ◽

10.1071/sb14034 ◽

2014 ◽

Vol 27 (6) ◽

pp. 450 ◽

Cited By ~ 4

Author(s):

Ian R. H. Telford ◽

Kanchana Pruesapan ◽

Peter C. van Welzen ◽

Jeremy J. Bruhl

Keyword(s):

Molecular Analysis ◽

Floral Morphology ◽

Sequence Data ◽

Conservation Status ◽

Molecular Data ◽

New Combination ◽

Its Sequence

Molecular analysis of the newly reinstated genus Synostemon F.Muell. (Phyllanthaceae, Phyllantheae), using ITS sequence data from the now densely sampled genus, confirmed that the previously recognised ‘Queensland clade’ consists of Synostemon albiflorus (F.Muell. ex Müll.Arg.) Airy Shaw, S. sphenophyllus Airy Shaw, Sauropus podenzanae (S.Moore) Airy Shaw and the undescribed Synostemon spinescens, sp. nov. ined., the latter being validated here as S. spinosus I.Telford & J.J.Bruhl. Morphological synapomorphies for the clade are as follows: linear, apiculate anthers that are connivent but only basally connate, and thickened, clavate, recurved stigmas. A new combination is provided under Synostemon for Sauropus podenzanae as Synostemon podenzanae (S.Moore) I.Telford & Pruesapan and Sauropus convallarioides J.T.Hunter & J.J.Bruhl is formally placed in synonymy under Synostemon sphenophyllus. Descriptions, distributional data and notes on ecology and conservation status are provided for these species. Phyllanthus albiflorus F.Muell. ex Müll.Arg., the basionym of Synostemon albiflorus, is lectotypified.

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Implementation of eHealth and AI integrated diagnostics with multidisciplinary digitized data: are we ready from an international perspective?

European Radiology ◽

10.1007/s00330-020-06874-x ◽

2020 ◽

Vol 30 (10) ◽

pp. 5510-5524 ◽

Cited By ~ 3

Author(s):

Mark Bukowski ◽

Robert Farkas ◽

Oya Beyan ◽

Lorna Moll ◽

Horst Hahn ◽

...

Keyword(s):

Data Integration ◽

Data Privacy ◽

Clinical Chemistry ◽

International Perspective ◽

Current Data ◽

Security And Privacy ◽

Ethical Challenges ◽

Medical Environment ◽

Key Points ◽

Integrated Diagnostics

Abstract Digitization of medicine requires systematic handling of the increasing amount of health data to improve medical diagnosis. In this context, the integration of the versatile diagnostic information, e.g., from anamnesis, imaging, histopathology, and clinical chemistry, and its comprehensive analysis by artificial intelligence (AI)–based tools is expected to improve diagnostic precision and the therapeutic conduct. However, the complex medical environment poses a major obstacle to the translation of integrated diagnostics into clinical research and routine. There is a high need to address aspects like data privacy, data integration, interoperability standards, appropriate IT infrastructure, and education of staff. Besides this, a plethora of technical, political, and ethical challenges exists. This is complicated by the high diversity of approaches across Europe. Thus, we here provide insights into current international activities on the way to digital comprehensive diagnostics. This includes a technical view on challenges and solutions for comprehensive diagnostics in terms of data integration and analysis. Current data communications standards and common IT solutions that are in place in hospitals are reported. Furthermore, the international hospital digitalization scoring and the European funding situation were analyzed. In addition, the regional activities in radiomics and the related publication trends are discussed. Our findings show that prerequisites for comprehensive diagnostics have not yet been sufficiently established throughout Europe. The manifold activities are characterized by a heterogeneous digitization progress and they are driven by national efforts. This emphasizes the importance of clear governance, concerted investments, and cooperation at various levels in the health systems. Key Points • Europe is characterized by heterogeneity in its digitization progress with predominantly national efforts. Infrastructural prerequisites for comprehensive diagnostics are not given and not sufficiently funded throughout Europe, which is particularly true for data integration. • The clinical establishment of comprehensive diagnostics demands for a clear governance, significant investments, and cooperation at various levels in the healthcare systems. • While comprehensive diagnostics is on its way, concerted efforts should be taken in Europe to get consensus concerning interoperability and standards, security, and privacy as well as ethical and legal concerns.

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Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy

Human Reproduction ◽

10.1093/humrep/deaa187 ◽

2020 ◽

Vol 35 (10) ◽

pp. 2237-2244 ◽

Cited By ~ 2

Author(s):

A Äyräväinen ◽

A Pasanen ◽

T Ahvenainen ◽

T Heikkinen ◽

P Pakarinen ◽

...

Keyword(s):

Conflicts Of Interest ◽

Tumour Size ◽

Fumarate Hydratase ◽

Clinical Information ◽

Molecular Data ◽

Uterine Leiomyomas ◽

Driver Mutations ◽

Wild Type ◽

Middle Aged ◽

Aged Patients

Abstract STUDY QUESTION What are the distributions and associated clinical characteristics of mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2) and fumarate hydratase (FH) aberrations in uterine leiomyomas from fertile-aged myomectomy patients? SUMMARY ANSWER These driver mutations account for the majority (83%) of tumours in fertile-aged patients. WHAT IS KNOWN ALREADY Alterations affecting MED12, HMGA2 and FH account for 80–90% of uterine leiomyomas from middle-aged hysterectomy patients, while the molecular background of tumours from young myomectomy patients has not been systematically studied. STUDY DESIGN, SIZE, DURATION A retrospective series of 361 archival uterine leiomyoma samples from 234 women aged ≤45 years undergoing myomectomy in 2009–2014 was examined. Associations between the molecular data and detailed clinical information of the patients and tumours were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS DNA was extracted from formalin-fixed paraffin-embedded samples and MED12 exons 1 and 2 were sequenced to identify mutations. Level of HMGA2 expression was evaluated by immunohistochemistry. Biallelic FH inactivation was analysed with 2-succinylcysteine staining, which is an indirect method of assessing FH deficiency. All patients’ medical histories were reviewed, and clinical information of patients and tumours was combined with molecular data. MAIN RESULTS AND THE ROLE OF CHANCE The median age at operation was 34 years. The majority (58%) of patients were operated on for a single leiomyoma. Known driver mutations were identified in 83% of tumours (71% MED12; 9% HMGA2; 3% FH). In solitary leiomyomas, the MED12 mutation frequency was only 43%, and 29% were wild-type for all driver alterations. MED12 mutations were associated with multiple tumours, smaller tumour size and subserosal location. LIMITATIONS, REASONS FOR CAUTION Although comprehensive, the study is retrospective in nature and all samples have been collected for routine diagnostic purposes. The use of paraffin-embedded samples and immunohistochemistry may have led to an underestimation of mutations. Due to the limited sample size and rarity of especially FH-deficient leiomyomas, the data are partly descriptive. WIDER IMPLICATIONS OF THE FINDINGS The contribution of driver mutations in leiomyomas from young myomectomy patients is comparable to tumours obtained from hysterectomies of mostly middle-aged women. Our results support the earlier findings that MED12 mutations are associated with multiple tumours, smaller tumour size and subserosal location. The study emphasizes the distinct molecular background of solitary leiomyomas, and more research is needed to clarify the underlying causes of the notable proportion of wild-type leiomyomas. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Academy of Finland (307773), the Sigrid Jusélius Foundation, the Cancer Foundation Finland and the iCAN Digital Precision Cancer Medicine Flagship. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A

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