Search

Quantifying an individual's risk for common diseases is an important goal of precision health. The polygenic risk score (PRS), which aggregates multiple risk alleles of candidate diseases, has emerged as a standard approach for identifying high-risk individuals. Although several studies have been performed to benchmark the PRS calculation tools and assess their potential to guide future clinical applications, some issues remain to be further investigated, such as lacking (i) various simulated data with different genetic effects; (ii) evaluation of machine learning models and (iii) evaluation on multiple ancestries studies. In this study, we systematically validated and compared 13 statistical methods, 5 machine learning models and 2 ensemble models using simulated data with additive and genetic interaction models, 22 common diseases with internal training sets, 4 common diseases with external summary statistics and 3 common diseases for trans -ancestry studies in UK Biobank. The statistical methods were better in simulated data from additive models and machine learning models have edges for data that include genetic interactions. Ensemble models are generally the best choice by integrating various statistical methods. LDpred2 outperformed the other standalone tools, whereas PRS-CS, lassosum and DBSLMM showed comparable performance. We also identified that disease heritability strongly affected the predictive performance of all methods. Both the number and effect sizes of risk SNPs are important; and sample size strongly influences the performance of all methods. For the trans -ancestry studies, we found that the performance of most methods became worse when training and testing sets were from different populations. [ABSTRACT FROM AUTHOR]

Background: Linked-read sequencing technologies generate high-base quality short reads that contain extrapolative information on long-range DNA connectedness. These advantages of linked-read technologies are well known and have been demonstrated in many human genomic and metagenomic studies. However, existing linked-read analysis pipelines (e.g., Long Ranger) were primarily developed to process sequencing data from the human genome and are not suited for analyzing metagenomic sequencing data. Moreover, linked-read analysis pipelines are typically limited to 1 specific sequencing platform., Findings: To address these limitations, we present the Linked-Read ToolKit (LRTK), a unified and versatile toolkit for platform agnostic processing of linked-read sequencing data from both human genome and metagenome. LRTK provides functions to perform linked-read simulation, barcode sequencing error correction, barcode-aware read alignment and metagenome assembly, reconstruction of long DNA fragments, taxonomic classification and quantification, and barcode-assisted genomic variant calling and phasing. LRTK has the ability to process multiple samples automatically and provides users with the option to generate reproducible reports during processing of raw sequencing data and at multiple checkpoints throughout downstream analysis. We applied LRTK on linked reads from simulation, mock community, and real datasets for both human genome and metagenome. We showcased LRTK's ability to generate comparative performance results from preceding benchmark studies and to report these results in publication-ready HTML document plots., Conclusions: LRTK provides comprehensive and flexible modules along with an easy-to-use Python-based workflow for processing linked-read sequencing datasets, thereby filling the current gap in the field caused by platform-centric genome-specific linked-read data analysis tools., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)