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Assessing the clinical utility of genetic profiling in fracture risk prediction: a decision curve analysis

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Abstract

Summary

Using decision curve analysis on 2188 women and 1324 men, we found that an osteogenomic profile constructed from 62 genetic variants improved the clinical net benefit of fracture risk prediction over and above that of clinical risk factors and BMD.

Introduction

Genetic profiling is a promising tool for assessing fracture risk. This study sought to use the decision curve analysis (DCA), a novel approach to determine the impact of genetic profiling on fracture risk prediction.

Methods

The study involved 2188 women and 1324 men, aged 60 years and above, who were followed for up to 23 years. Bone mineral density (BMD) and clinical risk factors were obtained at baseline. The incidence of fracture and mortality were recorded. A weighted individual genetic risk score (GRS) was constructed from 62 BMD-associated genetic variants. Four models were considered: CRF (clinical risk factors); CRF + GRS; Garvan model (GFRC) including CRF and femoral neck BMD; and GFRC + GRS. The DCA was used to evaluate the clinical net benefit of predictive models at a range of clinically reasonable risk thresholds.

Results

In both women and men, the full model GFRC + GRS achieved the highest net benefits. For 10-year risk threshold > 18% for women and > 15% for men, the GRS provided net benefit above those of the CRF models. At 20% risk threshold, adding the GRS could help to avoid 1 additional treatment per 81 women or 1 per 24 men compared with the Garvan model. At lower risk thresholds, there was no significant difference between the four models.

Conclusions

The addition of genetic profiling into the clinical risk factors can improve the net clinical benefit at higher risk thresholds of fracture. Although the contribution of genetic profiling was modest in the presence of BMD + CRF, it appeared to be able to replace BMD for fracture prediction.

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Acknowledgements

The authors gratefully acknowledge the expert assistance of Janet Watters, Donna Reeves, Shaye Field, and Jodie Rattey in the interview, data collection, and measurement of bone densitometry, and the invaluable help of the Dubbo Base Hospital radiology staff, PRP Radiology, and Orana radiology. We thank the IT group of the Garvan Institute of Medical Research for help in managing the data. This work was partly supported by the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, Australia

    T. P. Ho-Le, J. R. Center, J. A. Eisman & T. V. Nguyen

  2. Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, Australia

    T. P. Ho-Le & H. T. Nguyen

  3. Faculty of Engineering and Information Technology, Hatinh University, Hatinh, Vietnam

    T. P. Ho-Le & H. T. T. Tran

  4. St Vincent Clinical School, UNSW Sydney, Sydney, Australia

    J. R. Center, J. A. Eisman & T. V. Nguyen

  5. School of Medicine Sydney, University of Notre Dame Australia, Sydney, Australia

    J. A. Eisman & T. V. Nguyen

  6. School of Biomedical Engineering, University of Technology, Sydney, Australia

    T. V. Nguyen

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  1. T. P. Ho-Le
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  2. H. T. T. Tran
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  3. J. R. Center
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Correspondence to T. V. Nguyen.

Ethics declarations

St Vincent’s Campus Research Ethics Committee approved the study protocol, and written informed consent was obtained from every participant.

Conflicts of interest

Professor John A. Eisman has served as consultant on Scientific Advisory Boards for Amgen, Eli Lilly, Merck Sharp & Dohme, Novartis, Sanofi-Aventis, Servier, and deCode. Professor J.R. Center has given educational talks for and received travel expenses from Amgen, Merck Sharp & Dohme, Novartis, and Sanofi-Aventis. She has received travel expenses from Merck Sharp & Dohme, Amgen, and Aspen. Professor Tuan V. Nguyen has received honoraria for consulting and speaking in symposia sponsored by Merck Sharp & Dohme, Roche, Sanofi-Aventis, Novartis, and Bridge Healthcare Pty Ltd. (Vietnam). Professor J. A. Eisman, Professor T. V. Nguyen, and Professor J. R. Center have received grants from Sanofi and BUPA. Professor T. V. Nguyen has received an NHMRC project grant. Thao P. Ho-Le received the Christine & T. Jack Martin Research travel grant from AMGEN and Australian and New Zealand Bone and Mineral Society. Other authors declare that they have no conflicts of interest.

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Ho-Le, T.P., Tran, H.T.T., Center, J.R. et al. Assessing the clinical utility of genetic profiling in fracture risk prediction: a decision curve analysis. Osteoporos Int 32, 271–280 (2021). https://doi.org/10.1007/s00198-020-05403-2

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