scholarly journals ShapeGTB: the role of local DNA shape in prioritization of functional variants in human promoters with machine learning

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5742 ◽  
Author(s):  
Maja Malkowska ◽  
Julian Zubek ◽  
Dariusz Plewczynski ◽  
Lucjan S. Wyrwicz
Keyword(s):  
Machine Learning ◽  
External Validation ◽  
Gc Content ◽  
Nucleotide Polymorphisms ◽  
Average Precision ◽  
Promoter Regions ◽  
Functional Sequence ◽  
Functional Variants ◽  
Local Sequence ◽  
Dna Shape

MotivationThe identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes.ResultsWe demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional single nucleotide polymorphisms within promoter regions—ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (average precision 0.93 vs. 0.47–0.55). On the external validation set based on ClinVar database it displayed worse performance but was still competitive with other methods (average precision 0.47 vs. 0.23–0.42). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future.

scholarly journals ShapeGTB: The role of local DNA shape in prioritization of functional variants in human promoters with machine learning

2018 ◽  
Author(s):  
Maja Malkowska ◽  
Julian Zubek ◽  
Dariusz Plewczynski ◽  
Lucjan S Wyrwicz
Keyword(s):  
Machine Learning ◽  
External Validation ◽  
Gc Content ◽  
Promoter Regions ◽  
Functional Sequence ◽  
Functional Variants ◽  
Local Sequence ◽  
Validation Set ◽  
Dna Shape ◽  
Coding Variants

Motivation: The identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes. Results: We demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional SNPs within promoter regions – ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (AUC ROC 0.97 vs. 0.57-0.59). On the external validation set based on ClinVar database it displayed only slightly worse performance (AUC ROC 0.92 vs. 0.74-0.81). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future. Availability and implementation: The datasets and source code are publicly available at: https://github.com/zubekj/ShapeGTB.

scholarly journals ShapeGTB: The role of local DNA shape in prioritization of functional variants in human promoters with machine learning

2018 ◽  
Author(s):  
Maja Malkowska ◽  
Julian Zubek ◽  
Dariusz Plewczynski ◽  
Lucjan S Wyrwicz
Keyword(s):  
Machine Learning ◽  
External Validation ◽  
Gc Content ◽  
Promoter Regions ◽  
Functional Sequence ◽  
Functional Variants ◽  
Local Sequence ◽  
Validation Set ◽  
Dna Shape ◽  
Coding Variants

Motivation: The identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes. Results: We demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional SNPs within promoter regions – ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (AUC ROC 0.97 vs. 0.57-0.59). On the external validation set based on ClinVar database it displayed only slightly worse performance (AUC ROC 0.92 vs. 0.74-0.81). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future. Availability and implementation: The datasets and source code are publicly available at: https://github.com/zubekj/ShapeGTB.

scholarly journals Single-Nucleotide Polymorphisms Sequencing Identifies Candidate Functional Variants at Prostate Cancer Risk Loci

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 547 ◽  
Author(s):  
Peng Zhang ◽  
Lori S. Tillmans ◽  
Stephen N. Thibodeau ◽  
Liang Wang
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Single Nucleotide Polymorphisms ◽  
Protein Binding ◽  
Prostate Cancer Risk ◽  
Sequencing Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Functional Variants ◽  
Dependent Protein

Genome-wide association studies have identified over 150 risk loci that increase prostate cancer risk. However, few causal variants and their regulatory mechanisms have been characterized. In this study, we utilized our previously developed single-nucleotide polymorphisms sequencing (SNPs-seq) technology to test allele-dependent protein binding at 903 SNP sites covering 28 genomic regions. All selected SNPs have shown significant cis-association with at least one nearby gene. After preparing nuclear extract using LNCaP cell line, we first mixed the extract with dsDNA oligo pool for protein–DNA binding incubation. We then performed sequencing analysis on protein-bound oligos. SNPs-seq analysis showed protein-binding differences (>1.5-fold) between reference and variant alleles in 380 (42%) of 903 SNPs with androgen treatment and 403 (45%) of 903 SNPs without treatment. From these significant SNPs, we performed a database search and further narrowed down to 74 promising SNPs. To validate this initial finding, we performed electrophoretic mobility shift assay in two SNPs (rs12246440 and rs7077275) at CTBP2 locus and one SNP (rs113082846) at NCOA4 locus. This analysis showed that all three SNPs demonstrated allele-dependent protein-binding differences that were consistent with the SNPs-seq. Finally, clinical association analysis of the two candidate genes showed that CTBP2 was upregulated, while NCOA4 was downregulated in prostate cancer (p < 0.02). Lower expression of CTBP2 was associated with poor recurrence-free survival in prostate cancer. Utilizing our experimental data along with bioinformatic tools provides a strategy for identifying candidate functional elements at prostate cancer susceptibility loci to help guide subsequent laboratory studies.

scholarly journals Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

2021 ◽  
Vol 7 (3) ◽  
pp. 47
Author(s):  
Marios Lange ◽  
Rodiola Begolli ◽  
Antonis Giakountis
Keyword(s):  
Disease Onset ◽  
Cancer Genome ◽  
Driver Mutations ◽  
Nucleotide Polymorphisms ◽  
Structural Variations ◽  
Coding Regions ◽  
Functional Variants ◽  
Coding Variants ◽  
Clinical Potential

The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.

scholarly journals Systematic literature review of machine learning methods used in the analysis of real-world data for patient-provider decision making

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Alan Brnabic ◽  
Lisa M. Hess
Keyword(s):  
Machine Learning ◽  
Decision Making ◽  
Literature Review ◽  
Systematic Literature Review ◽  
Real World ◽  
Learning Algorithms ◽  
External Validation ◽  
Machine Learning Algorithms ◽  
Learning Methods ◽  
Machine Learning Methods

Abstract Background Machine learning is a broad term encompassing a number of methods that allow the investigator to learn from the data. These methods may permit large real-world databases to be more rapidly translated to applications to inform patient-provider decision making. Methods This systematic literature review was conducted to identify published observational research of employed machine learning to inform decision making at the patient-provider level. The search strategy was implemented and studies meeting eligibility criteria were evaluated by two independent reviewers. Relevant data related to study design, statistical methods and strengths and limitations were identified; study quality was assessed using a modified version of the Luo checklist. Results A total of 34 publications from January 2014 to September 2020 were identified and evaluated for this review. There were diverse methods, statistical packages and approaches used across identified studies. The most common methods included decision tree and random forest approaches. Most studies applied internal validation but only two conducted external validation. Most studies utilized one algorithm, and only eight studies applied multiple machine learning algorithms to the data. Seven items on the Luo checklist failed to be met by more than 50% of published studies. Conclusions A wide variety of approaches, algorithms, statistical software, and validation strategies were employed in the application of machine learning methods to inform patient-provider decision making. There is a need to ensure that multiple machine learning approaches are used, the model selection strategy is clearly defined, and both internal and external validation are necessary to be sure that decisions for patient care are being made with the highest quality evidence. Future work should routinely employ ensemble methods incorporating multiple machine learning algorithms.

scholarly journals An approach using ddRADseq and machine learning for understanding speciation in Antarctic Antarctophilinidae gastropods

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Juan Moles ◽  
Shahan Derkarabetian ◽  
Stefano Schiaparelli ◽  
Michael Schrödl ◽  
Jesús S. Troncoso ◽  
...  
Keyword(s):  
Machine Learning ◽  
Deep Sea ◽  
Weddell Sea ◽  
Nucleotide Polymorphisms ◽  
Sea Levels ◽  
Suitable Material ◽  
Genetic Lineages ◽  
Genome Wide ◽  
Gastropod Mollusks ◽  
Double Digestion

AbstractSampling impediments and paucity of suitable material for molecular analyses have precluded the study of speciation and radiation of deep-sea species in Antarctica. We analyzed barcodes together with genome-wide single nucleotide polymorphisms obtained from double digestion restriction site-associated DNA sequencing (ddRADseq) for species in the family Antarctophilinidae. We also reevaluated the fossil record associated with this taxon to provide further insights into the origin of the group. Novel approaches to identify distinctive genetic lineages, including unsupervised machine learning variational autoencoder plots, were used to establish species hypothesis frameworks. In this sense, three undescribed species and a complex of cryptic species were identified, suggesting allopatric speciation connected to geographic or bathymetric isolation. We further observed that the shallow waters around the Scotia Arc and on the continental shelf in the Weddell Sea present high endemism and diversity. In contrast, likely due to the glacial pressure during the Cenozoic, a deep-sea group with fewer species emerged expanding over great areas in the South-Atlantic Antarctic Ridge. Our study agrees on how diachronic paleoclimatic and current environmental factors shaped Antarctic communities both at the shallow and deep-sea levels, promoting Antarctica as the center of origin for numerous taxa such as gastropod mollusks.

scholarly journals Development of a machine learning model for predicting pediatric mortality in the early stages of intensive care unit admission

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bongjin Lee ◽  
Kyunghoon Kim ◽  
Hyejin Hwang ◽  
You Sun Kim ◽  
Eun Hee Chung ◽  
...  
Keyword(s):  
Machine Learning ◽  
Intensive Care Unit ◽  
Intensive Care ◽  
Validation Cohort ◽  
External Validation ◽  
Learning Model ◽  
Derivation Cohort ◽  
Icu Admission ◽  
Early Stages ◽  
Machine Learning Model

AbstractThe aim of this study was to develop a predictive model of pediatric mortality in the early stages of intensive care unit (ICU) admission using machine learning. Patients less than 18 years old who were admitted to ICUs at four tertiary referral hospitals were enrolled. Three hospitals were designated as the derivation cohort for machine learning model development and internal validation, and the other hospital was designated as the validation cohort for external validation. We developed a random forest (RF) model that predicts pediatric mortality within 72 h of ICU admission, evaluated its performance, and compared it with the Pediatric Index of Mortality 3 (PIM 3). The area under the receiver operating characteristic curve (AUROC) of RF model was 0.942 (95% confidence interval [CI] = 0.912–0.972) in the derivation cohort and 0.906 (95% CI = 0.900–0.912) in the validation cohort. In contrast, the AUROC of PIM 3 was 0.892 (95% CI = 0.878–0.906) in the derivation cohort and 0.845 (95% CI = 0.817–0.873) in the validation cohort. The RF model in our study showed improved predictive performance in terms of both internal and external validation and was superior even when compared to PIM 3.

scholarly journals External validation of an opioid misuse machine learning classifier in hospitalized adult patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Majid Afshar ◽  
Brihat Sharma ◽  
Sameer Bhalla ◽  
Hale M. Thompson ◽  
Dmitriy Dligach ◽  
...  
Keyword(s):  
Machine Learning ◽  
Screening Program ◽  
External Validation ◽  
Hospital Setting ◽  
Opioid Misuse ◽  
Original Cohort ◽  
Learning Classifier ◽  
Observational Cohort ◽  
Drug Abuse Screening Test ◽  
Screening Barriers

Abstract Background Opioid misuse screening in hospitals is resource-intensive and rarely done. Many hospitalized patients are never offered opioid treatment. An automated approach leveraging routinely captured electronic health record (EHR) data may be easier for hospitals to institute. We previously derived and internally validated an opioid classifier in a separate hospital setting. The aim is to externally validate our previously published and open-source machine-learning classifier at a different hospital for identifying cases of opioid misuse. Methods An observational cohort of 56,227 adult hospitalizations was examined between October 2017 and December 2019 during a hospital-wide substance use screening program with manual screening. Manually completed Drug Abuse Screening Test served as the reference standard to validate a convolutional neural network (CNN) classifier with coded word embedding features from the clinical notes of the EHR. The opioid classifier utilized all notes in the EHR and sensitivity analysis was also performed on the first 24 h of notes. Calibration was performed to account for the lower prevalence than in the original cohort. Results Manual screening for substance misuse was completed in 67.8% (n = 56,227) with 1.1% (n = 628) identified with opioid misuse. The data for external validation included 2,482,900 notes with 67,969 unique clinical concept features. The opioid classifier had an AUC of 0.99 (95% CI 0.99–0.99) across the encounter and 0.98 (95% CI 0.98–0.99) using only the first 24 h of notes. In the calibrated classifier, the sensitivity and positive predictive value were 0.81 (95% CI 0.77–0.84) and 0.72 (95% CI 0.68–0.75). For the first 24 h, they were 0.75 (95% CI 0.71–0.78) and 0.61 (95% CI 0.57–0.64). Conclusions Our opioid misuse classifier had good discrimination during external validation. Our model may provide a comprehensive and automated approach to opioid misuse identification that augments current workflows and overcomes manual screening barriers.

scholarly journals Proposing a machine-learning based method to predict stillbirth before and during delivery and ranking the features: nationwide retrospective cross-sectional study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Toktam Khatibi ◽  
Elham Hanifi ◽  
Mohammad Mehdi Sepehri ◽  
Leila Allahqoli
Keyword(s):  
Machine Learning ◽  
External Validation ◽  
Fetal Loss ◽  
Null Distribution ◽  
Training Dataset ◽  
Gradient Boosting ◽  
Support Vector ◽  
Cross Sectional ◽  
Boosting Method ◽  
Demographic Features

Abstract Background Stillbirth is defined as fetal loss in pregnancy beyond 28 weeks by WHO. In this study, a machine-learning based method is proposed to predict stillbirth from livebirth and discriminate stillbirth before and during delivery and rank the features. Method A two-step stack ensemble classifier is proposed for classifying the instances into stillbirth and livebirth at the first step and then, classifying stillbirth before delivery from stillbirth during the labor at the second step. The proposed SE has two consecutive layers including the same classifiers. The base classifiers in each layer are decision tree, Gradient boosting classifier, logistics regression, random forest and support vector machines which are trained independently and aggregated based on Vote boosting method. Moreover, a new feature ranking method is proposed in this study based on mean decrease accuracy, Gini Index and model coefficients to find high-ranked features. Results IMAN registry dataset is used in this study considering all births at or beyond 28th gestational week from 2016/04/01 to 2017/01/01 including 1,415,623 live birth and 5502 stillbirth cases. A combination of maternal demographic features, clinical history, fetal properties, delivery descriptors, environmental features, healthcare service provider descriptors and socio-demographic features are considered. The experimental results show that our proposed SE outperforms the compared classifiers with the average accuracy of 90%, sensitivity of 91%, specificity of 88%. The discrimination of the proposed SE is assessed and the average AUC of ±95%, CI of 90.51% ±1.08 and 90% ±1.12 is obtained on training dataset for model development and test dataset for external validation, respectively. The proposed SE is calibrated using isotopic nonparametric calibration method with the score of 0.07. The process is repeated 10,000 times and AUC of SE classifiers using random different training datasets as null distribution. The obtained p-value to assess the specificity of the proposed SE is 0.0126 which shows the significance of the proposed SE. Conclusions Gestational age and fetal height are two most important features for discriminating livebirth from stillbirth. Moreover, hospital, province, delivery main cause, perinatal abnormality, miscarriage number and maternal age are the most important features for classifying stillbirth before and during delivery.

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