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- Title
Variability in performance of genetic-enhanced DXA-BMD prediction models across diverse ethnic and geographic populations: A risk prediction study.
- Authors
Liu, Yong; Meng, Xiang-He; Wu, Chong; Su, Kuan-Jui; Liu, Anqi; Tian, Qing; Zhao, Lan-Juan; Qiu, Chuan; Luo, Zhe; Gonzalez-Ramirez, Martha I; Shen, Hui; Xiao, Hong-Mei; Deng, Hong-Wen
- Abstract
Background: Osteoporosis is a major global health issue, weakening bones and increasing fracture risk. Dual-energy X-ray absorptiometry (DXA) is the standard for measuring bone mineral density (BMD) and diagnosing osteoporosis, but its costliness and complexity impede widespread screening adoption. Predictive modeling using genetic and clinical data offers a cost-effective alternative for assessing osteoporosis and fracture risk. This study aims to develop BMD prediction models using data from the UK Biobank (UKBB) and test their performance across different ethnic and geographical populations. Methods and findings: We developed BMD prediction models for the femoral neck (FNK) and lumbar spine (SPN) using both genetic variants and clinical factors (such as sex, age, height, and weight), within 17,964 British white individuals from UKBB. Models based on regression with least absolute shrinkage and selection operator (LASSO), selected based on the coefficient of determination (R2) from a model selection subset of 5,973 individuals from British white population. These models were tested on 5 UKBB test sets and 12 independent cohorts of diverse ancestries, totaling over 15,000 individuals. Furthermore, we assessed the correlation of predicted BMDs with fragility fractures risk in 10 years in a case-control set of 287,183 European white participants without DXA-BMDs in the UKBB. With single-nucleotide polymorphism (SNP) inclusion thresholds at 5×10−6 and 5×10−7, the prediction models for FNK-BMD and SPN-BMD achieved the highest R2 of 27.70% with a 95% confidence interval (CI) of [27.56%, 27.84%] and 48.28% (95% CI [48.23%, 48.34%]), respectively. Adding genetic factors improved predictions slightly, explaining an additional 2.3% variation for FNK-BMD and 3% for SPN-BMD over clinical factors alone. Survival analysis revealed that the predicted FNK-BMD and SPN-BMD were significantly associated with fragility fracture risk in the European white population (P < 0.001). The hazard ratios (HRs) of the predicted FNK-BMD and SPN-BMD were 0.83 (95% CI [0.79, 0.88], corresponding to a 1.44% difference in 10-year absolute risk) and 0.72 (95% CI [0.68, 0.76], corresponding to a 1.64% difference in 10-year absolute risk), respectively, indicating that for every increase of one standard deviation in BMD, the fracture risk will decrease by 17% and 28%, respectively. However, the model's performance declined in other ethnic groups and independent cohorts. The limitations of this study include differences in clinical factors distribution and the use of only SNPs as genetic factors. Conclusions: In this study, we observed that combining genetic and clinical factors improves BMD prediction compared to clinical factors alone. Adjusting inclusion thresholds for genetic variants (e.g., 5×10−6 or 5×10−7) rather than solely considering genome-wide association study (GWAS)-significant variants can enhance the model's explanatory power. The study highlights the need for training models on diverse populations to improve predictive performance across various ethnic and geographical groups. Yong Liu and co-workers compare Author summary: Why was this study done?: Osteoporosis diagnosis via bone mineral density (BMD) measurements by dual-energy X-ray absorptiometry (DXA) is impractical for large-scale screening, especially in resource-limited areas. Genomic data offers a cost-effective alternative for predicting disease risk, but current methods often overlook sub-significant variants and clinical factors. Most existing genomic prediction methods are based on European ancestry, with limited evaluation in other ethnic populations. What did the researchers do and find?: We developed BMD prediction models for femoral neck (FNK) and lumbar spine (SPN) using a training set of 17,964 individuals from British white ancestry in UK Biobank (UKBB), integrating clinical and genetic factors. We observed that strong correlations between predicted and true BMDs (R2≈25% for FNK-BMD and R2≈45% for SPN-BMD) and significant associations with fracture risk in European ancestry populations. And we identified the optimal P-value thresholds for FNK-BMD (5×10−6) and SPN-BMD (5×10−7), noting that these thresholds vary by trait and sample size. By applying the prediction models on 5 UKBB test sets and 12 independent cohorts of diverse ancestries, totaling over 15,000 individuals, we observed that the BMD prediction models performed well in UKBB European populations but less effectively in other ancestry groups and independent cohorts. What do these findings mean?: We show that genetic factors could improve the performance of DXA-BMD prediction. Within the same population, the predicted BMDs can help prioritize individuals at high risk of fragility fracture for tailored treatments. Genetic prediction methods need rigorous evaluation before application to different populations, emphasizing the importance of diverse population training. Study limitations include differences in the distribution of clinical factors such as sex and age between the UKBB data sets and the independent cohorts, as well as the inclusion of only single-nucleotide polymorphisms (SNPs) as genetic factors.
- Subjects
BONE density; DUAL-energy X-ray absorptiometry; RESOURCE-limited settings; GENOME-wide association studies; FEMUR neck; BONE fractures
- Publication
PLoS Medicine, 2024, Vol 21, Issue 8, p1
- ISSN
1549-1277
- Publication type
Article
- DOI
10.1371/journal.pmed.1004451