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• W2892262505 abstract "Background Genomics-based prediction could be useful since genome-wide genotyping costs less than many clinical tests. We tested whether machine learning methods could provide a clinically-relevant genomic prediction of quantitative ultrasound speed of sound (SOS)—a risk factor for osteoporotic fracture. Methods We used 341,449 individuals from UK Biobank with SOS measures to develop genomically-predicted SOS (gSOS) using machine learning algorithms. We selected the optimal algorithm in 5,335 independent individuals and then validated it and its ability to predict incident fracture in an independent test dataset (N = 80,027). Finally, we explored whether genomic pre-screening could complement a UK-based osteoporosis screening strategy, based on the validated tool FRAX. Results gSOS explained 4.8-fold more variance in SOS than FRAX clinical risk factors (CRF) alone ( r 2 = 23% vs. 4.8%). A standard deviation decrease in gSOS, adjusting for the CRF-FRAX score was associated with a higher increased odds of incident major osteoporotic fracture (1,491 cases / 78,536 controls, OR = 1.91 [1.70-2.14], P = 10 -28 ) than that for measured SOS (OR = 1.60 [1.50-1.69], P = 10 -52 ) and femoral neck bone mineral density (147 cases / 4,594 controls, OR = 1.53 [1.27-1.83], P = 10 -6 ). Individuals in the bottom decile of the gSOS distribution had a 3.25-fold increased risk of major osteoporotic fracture (P = 10 -18 ) compared to the top decile. A gSOS-based FRAX score, identified individuals at high risk for incident major osteoporotic fractures better than the CRF-FRAX score (P = 10 -14 ). Introducing a genomic pre-screening step into osteoporosis screening in 4,741 individuals reduced the number of required clinical visits from 2,455 to 1,273 and the number of BMD tests from 1,013 to 473, while only reducing the sensitivity to identify individuals eligible for therapy from 99% to 95%. Interpretation The use of genotypes in a machine learning algorithm resulted in a clinically-relevant prediction of SOS and fracture, with potential to impact healthcare resource utilization. Research in Context Evidence Before this Study Genome-wide association studies have identified many loci associated with risk of clinically-relevant fracture risk factors, such as SOS. Yet, it is unclear if such information can be leveraged to identify those at risk for disease outcomes, such as osteoporotic fractures. Most previous attempts to predict disease risk from genotypes have used polygenic risk scores, which may not be optimal for genomic-prediction. Despite these obstacles, genomic-prediction could enable screening programs to be more efficient since most people screened in a population are not determined to have a level of risk that would prompt a change in clinical care. Genomic pre-screening could help identify individuals whose risk of disease is low enough that they are unlikely to benefit from screening. Added Value of this Study Using a large dataset of 426,811 individuals we trained and tested a machine learning algorithm to genomically-predict SOS. This metric, gSOS, had performance characteristics for predicting fracture risk that were similar to measured SOS and femoral neck BMD. Implementing a gSOS-based pre-screening step into the UK-based osteoporosis treatment guidelines reduced the number of individuals who would require screening clinical visits and skeletal testing by approximately 50%, while having little impact on the sensitivity to identify individuals at high risk for osteoporotic fracture. Implications of all of the Available Evidence Clinically-relevant genomic prediction of heritable traits is feasible using the machine learning algorithm presented here in large sample sizes. Genome-wide genotyping is now less expensive than many clinical tests, needs to be performed once over a lifetime and could risk stratify for multiple heritable traits and diseases years prior to disease onset, providing an opportunity for prevention. The implementation of such algorithms could improve screening efficiency, yet their cost-effectiveness will need to be ascertained in subsequent analyses." @default.
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• W2892262505 date "2018-09-11" @default.
• W2892262505 modified "2023-10-14" @default.
• W2892262505 title "Machine Learning to Predict Osteoporotic Fracture Risk from Genotypes" @default.
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• W2892262505 doi "https://doi.org/10.1101/413716" @default.
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