TADA—a machine learning tool for functional annotation-based prioritisation of pathogenic CNVs

Hertzberg, Jakob; Mundlos, Stefan; Vingron, Martin; Gallone, Giuseppe

doi:10.1186/s13059-022-02631-z

Cited by 10 publications

(14 citation statements)

References 62 publications

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“…Furthermore, POSTRE can analyze not only Copy Number Variants (CNVs) (i.e. deletions and duplications) (Hertzberg et al, 2022), but also balanced inversions and translocations. In this section we provide an overview of the tool (Figure 1a-c).…”

Section: Resultsmentioning

confidence: 99%

“…On the one hand, there are “annotation” tools that provide different layers of descriptive information for the genomic regions affected by the SVs (e.g. VEP (McLaren et al, 2016), ClinTAD (Spector and Wiita, 2019), TADA (Hertzberg et al, 2022), TADeus2 (Poszewiecka et al, 2022) or POSTRE). The type of provided information differs among tools, but can include: the genes directly affected or located close to the SV, the recurrence of SVs in the same locus for additional patients, the presence of cis -regulatory elements, etc.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, there are "prediction" tools that can rank and prioritize SVs based on their pathogenicity, although only a few of them consider both coding and long-range pathomechanisms (e.g. POSTRE, TADA (Hertzberg et al, 2022), TADeus2 (Poszewiecka et al, 2022), SVScore (Ganel et al, 2017)). A more detailed comparison between POSTRE and other available tools is presented in Table 4 and briefly discussed below.…”

Section: Postre Benchmarkingmentioning

confidence: 99%

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POSTRE: a tool to predict the pathological effects of human structural variants

Sánchez-Gaya

Rada-Iglesias

2022

Preprint

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Understanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Postre Benchmarkingmentioning

confidence: 99%

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POSTRE: a tool to predict the pathological effects of human structural variants

Sánchez-Gaya

Rada-Iglesias

2022

Preprint

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“…To evaluate the pathogenicity of a rearrangement uses the state-of-the-art, third-party software: TADA (available only for autosomes) ( 47 ) and ClassifyCNV ( 48 ) as well as an original statistical significance p-value.…”

Section: Methodsmentioning

confidence: 99%

`TADeus2`: a web server facilitating the clinical diagnosis by pathogenicity assessment of structural variations disarranging 3D chromatin structure

Poszewiecka

Pienkowski

Nowosad

et al. 2022

Nucleic Acids Research

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In recent years great progress has been made in identification of structural variants (SV) in the human genome. However, the interpretation of SVs, especially located in non-coding DNA, remains challenging. One of the reasons stems in the lack of tools exclusively designed for clinical SVs evaluation acknowledging the 3D chromatin architecture. Therefore, we present TADeus2 a web server dedicated for a quick investigation of chromatin conformation changes, providing a visual framework for the interpretation of SVs affecting topologically associating domains (TADs). This tool provides a convenient visual inspection of SVs, both in a continuous genome view as well as from a rearrangement’s breakpoint perspective. Additionally, TADeus2 allows the user to assess the influence of analyzed SVs within flaking coding/non-coding regions based on the Hi-C matrix. Importantly, the SVs pathogenicity is quantified and ranked using TADA, ClassifyCNV tools and sampling-based P-value. TADeus2 is publicly available at https://tadeus2.mimuw.edu.pl.

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“…Although functional annotation of CNVs has been considered in genome-wide annotation and the calculation of feature values has been done by counting or taking the mean, no statistics based on the deleterious significance of features have been presented. Several tools have been developed, but few of these tools predicted the pathogenicity of the five-tier classification of CNVs, such as X-CNV [ 11 ], ISV [ 12 ], StrVCTVRE [ 13 ] and TADA [ 14 ]. X-CNV is an approach to integrate diverse human genome information toward a quantitative measure of pathogenicity of CNVs on the whole genome-scale.…”

Section: Introductionmentioning

confidence: 99%

dbCNV: deleteriousness-based model to predict pathogenicity of copy number variations

Chen

Xiong

et al. 2023

BMC Genomics

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Background Copy number variation (CNV) is a type of structural variation, which is a gain or loss event with abnormal changes in copy number. Methods to predict the pathogenicity of CNVs are required to realize the relationship between these variants and clinical phenotypes. ClassifyCNV, X-CNV, StrVCTVRE, etc. have been trained to predict the pathogenicity of CNVs, but few studies have been reported based on the deleterious significance of features. Results From single nucleotide polymorphism (SNP), gene and region dimensions, we collected 79 informative features that quantitatively describe the characteristics of CNV, such as CNV length, the number of protein genes, the number of three prime untranslated region. Then, according to the deleterious significance, we formulated quantitative methods for features, which fall into two categories: the first is variable type, including maximum, minimum and mean; the second is attribute type, which is measured by numerical sum. We used Gradient Boosted Trees (GBT) algorithm to construct dbCNV, which can be used to predict pathogenicity for five-tier classification and binary classification of CNVs. We demonstrated that the distribution of most feature values was consistent with the deleterious significance. The five-tier classification model accuracy for 0.85 and 0.79 in loss and gain CNVs, which proved that it has high discrimination power in predicting the pathogenicity of five-tier classification CNVs. The binary model achieved area under curve (AUC) values of 0.96 and 0.81 in the validation set, respectively, in gain and loss CNVs. Conclusion The performance of the dbCNV suggest that functional deleteriousness-based model of CNV is a promising approach to support the classification prediction and to further understand the pathogenic mechanism.

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TADA—a machine learning tool for functional annotation-based prioritisation of pathogenic CNVs

Cited by 10 publications

References 62 publications

POSTRE: a tool to predict the pathological effects of human structural variants

POSTRE: a tool to predict the pathological effects of human structural variants

`TADeus2`: a web server facilitating the clinical diagnosis by pathogenicity assessment of structural variations disarranging 3D chromatin structure

dbCNV: deleteriousness-based model to predict pathogenicity of copy number variations

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TADA—a machine learning tool for functional annotation-based prioritisation of pathogenic CNVs

Cited by 10 publications

References 62 publications

POSTRE: a tool to predict the pathological effects of human structural variants

POSTRE: a tool to predict the pathological effects of human structural variants

TADeus2: a web server facilitating the clinical diagnosis by pathogenicity assessment of structural variations disarranging 3D chromatin structure

dbCNV: deleteriousness-based model to predict pathogenicity of copy number variations

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Product

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`TADeus2`: a web server facilitating the clinical diagnosis by pathogenicity assessment of structural variations disarranging 3D chromatin structure